HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells.

OBJECTIVE: Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. DESIGN: Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. RESULTS: NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. CONCLUSION: Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.

Towards a Standardized Classification of the Hepatobiliary Manifestations in Cystic Fibrosis (CFHBI): A Joint ESPGHAN/NASPGHAN Position Paper.

The broad spectrum of hepatobiliary involvement in cystic fibrosis (CF) has been commonly referred to as cystic fibrosis liver disease (CFLD). However, differences in the definitions of CFLD have led to variations in reported prevalence, incidence rates, and standardized recommendations for diagnosis and therapies. Harmonizing the description of the spectrum of hepatobiliary involvement in all people with CF (pwCF) is deemed essential for providing a reliable account of the natural history, which in turn supports the development of meaningful clinical outcomes in patient care and research. Recognizing this necessity, The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) commissioned and tasked a committee to develop and propose a systematic classification of the CF hepatobiliary manifestations to increase uniformity, accuracy, and comparability for clinical, registry, and research purposes. This report describes the committee's combined expert position statement on hepatobiliary involvement in CF, which has been endorsed by NASPGHAN and ESPGHAN. We recommend using CFHBI (Cystic Fibrosis Hepato-Biliary Involvement) as the updated term to describe and classify all hepatobiliary manifestations in all pwCF. CFHBI encompasses the current extensive spectrum of phenotypical, clinical, or diagnostic expressions of liver involvement observed in pwCF. We present a schematic categorization of CFHBI, which may also be used to track and classify the changes and development of CFHBI in pwCF over time. The proposed classification for CFHBI is based on expert consensus and has not been validated for clinical practice and research purposes. Achieving validation should be an important aim for future research.

SAGES guidelines for the use of laparoscopy during pregnancy.

BACKGROUND: When pregnant patients present with nonobstetric pathology, the physicians caring for them may be uncertain about the optimal management strategy. The aim of this guideline is to develop evidence-based recommendations for pregnant patients presenting with common surgical pathologies including appendicitis, biliary disease, and inflammatory bowel disease (IBD). METHODS: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Guidelines Committee convened a working group to address these issues. The group generated five key questions and completed a systematic review and meta-analysis of the literature. An expert panel then met to form evidence-based recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation approach. Expert opinion was utilized when the available evidence was deemed insufficient. RESULTS: The expert panel agreed on ten recommendations addressing the management of appendicitis, biliary disease, and IBD during pregnancy. CONCLUSIONS: Conditional recommendations were made in favor of appendectomy over nonoperative treatment of appendicitis, laparoscopic appendectomy over open appendectomy, and laparoscopic cholecystectomy over nonoperative treatment of biliary disease and acute cholecystitis specifically. Based on expert opinion, the panel also suggested either operative or nonoperative treatment of biliary diseases other than acute cholecystitis in the third trimester, endoscopic retrograde cholangiopancreatography rather than common bile duct exploration for symptomatic choledocholithiasis, applying the same criteria for emergent surgical intervention in pregnant and non-pregnant IBD patients, utilizing an open rather than minimally invasive approach for pregnant patients requiring emergent surgical treatment of IBD, and managing pregnant patients with active IBD flares in a multidisciplinary fashion at centers with IBD expertise.

The robotic-assisted laparoscopic approach to biliary tract resection and reconstruction for benign indications: A single-center experience.

BACKGROUND: Benign biliary disease (BBD) is a prevalent condition involving patients who require extrahepatic bile duct resections and reconstructions due to nonmalignant causes. METHODS: This study followed all patients who underwent biliary resections for BBD between 2015 and 2023. We excluded those with malignant conditions and patients who had an 'open' operation. Based on the patient's anatomy, the procedures employed were either robotic Roux-en-Y hepaticojejunostomy (RYHJ) or robotic choledochoduodenostomy (CDD). RESULTS: From the 33 patients studied, 23 were female, and 10 were male. Anesthesiology (ASA) class was 3 ± 0.5; the MELD score was 9 ± 4.1; the Child-Pugh score was 6 ± 1.7. The primary indications for undergoing the operation included iatrogenic bile duct injuries, biliary strictures, and type 1 choledochal cysts. The average surgical duration was about 272 min, and the average blood loss amounted to 79 mL. Postoperatively, three patients experienced major complications, all attributed to anastomotic leaks. The average hospital stay was 4 days, with a readmission rate of 15% within 30 days. During an average follow-up period of 33 months, one patient had to undergo a revision at 18 months due to stricture. This necessitated further duct resection and reanastomosis. Notably, there were no reported hepatectomies, no conversion to the 'open' method, no intraoperative complications, and no mortalities. CONCLUSIONS: Robotic extrahepatic bile duct resection and reconstruction with Roux-en-Y hepaticojejunostomy or choledochoduodenostomy is safe with an acceptable postoperative morbidity, short hospital length of stay, and low postoperative stricture rate at intermediate duration follow-up.

The multidisciplinary management of cholangiocarcinoma.

Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options.

Fungal infections and the fungal microbiome in hepatobiliary disorders.

Liver and biliary diseases affect more than a billion people worldwide, with high associated morbidity and mortality. The impact of the intestinal bacterial microbiome on liver diseases has been well established. However, the fungal microbiome, or mycobiome, has been overlooked for a long time. Recently, several studies have shed light on the role of the mycobiome in the development and progression of hepatobiliary diseases. In particular, the fungal genus Candida has been found to be involved in the pathogenesis of multiple hepatobiliary conditions. Herein, we compare colonisation and infection, describe mycobiome findings in the healthy state and across the various hepatobiliary conditions, and point toward communalities. We detail how quantitation of immune responses to fungal antigens can be employed to predict disease severity, e.g. using antibodies to Saccharomyces cerevisiae or specific anti-Candida albicans antibodies. We also show how fungal products (e.g. beta-glucans, candidalysin) activate the host's immune system to exacerbate liver and biliary diseases. Finally, we describe how the gut mycobiome can be modulated to ameliorate hepatobiliary conditions.

The exposome and liver disease - how environmental factors affect liver health.

Since the initial development of the exposome concept, much effort has been devoted to the characterisation of the exposome through analytical, epidemiological, and toxicological/mechanistic studies. There is now an urgent need to link the exposome to human diseases and to include exposomics in the characterisation of environment-linked pathologies together with genomics and other omics. Liver diseases are particularly well suited for such studies since major functions of the liver include the detection, detoxification, and elimination of xenobiotics, as well as inflammatory responses. It is well known that several liver diseases are associated with i) addictive behaviours such as alcohol consumption, smoking, and to a certain extent dietary imbalance and obesity, ii) viral and parasitic infections, and iii) exposure to toxins and occupational chemicals. Recent studies indicate that environmental exposures are also significantly associated with liver diseases, and these include air pollution (particulate matter and volatile chemicals), contaminants such as polyaromatic hydrocarbons, bisphenol A and per-and poly-fluorinated substances, and physical stressors such as radiation. Furthermore, microbial metabolites and the "gut-liver" axis play a major role in liver diseases. Exposomics is poised to play a major role in the field of liver pathology. Methodological advances such as the exposomics-metabolomics framework, the determination of risk factors' genomic and epigenomic signatures, and cross-species biological pathway analysis should further delineate the impact of the exposome on the liver, opening the way for improved prevention, as well as the identification of new biomarkers of exposure and effects, and additional therapeutic targets.

The Diagnostic Yield of Magnetic Resonance Cholangiopancreatography in the Setting of Acute Pancreaticobiliary Disease - A Single Center Experience.

PURPOSE: To discern whether preceding ultrasound (US) results, patient demographics and biochemical markers can be implemented as predictors of an abnormal Magnetic Resonance Cholangiopancreatography (MRCP) study in the context of acute pancreaticobiliary disease. METHODS: A retrospective study was performed assessing US results, age, gender, elevated lipase and biliary enzymes for consecutive patients who underwent an urgent MRCP following an initial US for acute pancreaticobiliary disease between January 2017-December 2018. Multivariable binary logistic regression models were constructed to assess for predictors of clinically significant MRCPs, and discrepant US/MRCP results. RESULTS: A total of 155 patients (mean age 56, 111 females) were included. Age (OR 1.03, P < 0.05), hyperlipasemia (OR 5.33, P < 0.05) and a positive US (OR 40.75, P < 0.05) were found to be independent predictors for a subsequent abnormal MRCP. Contrarily, gender and elevated biliary enzymes were not reliable predictors of an abnormal MRCP, or significant MRCP/US discrepancies. Of 66 cases (43%) of discordant US/MRCPs, half had clinically significant discrepant findings such as newly discovered choledocholithiasis and pancreaticobiliary neoplasia. Age was the sole predictor for a significant US/MRCP discrepancy, with 2% increase in the odds of a significant discrepancy per year of increase in age. CONCLUSION: An abnormal US, hyperlipasemia and increased age serve as predictors for a subsequent abnormal MRCP, as opposed to gender and biliary enzyme elevation. Age was the sole predictor of a significant US/MRCP discrepancy that provided new information which significantly impacted subsequent management. In the remaining cases, however, MRCP proved useful in reaffirming the clinical diagnosis and avoiding further investigations.

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study.

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

Associations of neopterin and kynurenine-tryptophan ratio with survival in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine-tryptophanratio (KT-ratio) in PSC. METHODS: Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. RESULTS: Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50-0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23-0.42) in all cohorts. CONCLUSIONS: Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts.

Epidemiology and risk factors for pyogenic liver abscess in the Calgary Health Zone revisited: a population-based study.

BACKGROUND: Pyogenic liver abscess (PLA), although uncommon in North America, is associated with significant morbidity and mortality. We sought to re-examine the epidemiology, risk factors, and outcomes of PLA in a large, diverse Canadian health zone. METHODS: All Calgary Health Zone (CHZ) residents aged ≥20 with PLA between 2015 and 2017 were identified. Incidence and mortality rates were calculated using census data. Risk factors for PLA were identified using a multivariate analysis. Data was compared to 1999-2003 data, also collected in the CHZ. RESULTS: There were 136 patients diagnosed with PLA between 2015 and 2017. Incidence rate during this period increased significantly relative to 1999-2003 (3.7 vs 2.3 cases/100,000 population, p < 0.01), however, mortality rates remained similar. The microbiological composition of PLA did not change over this 15-year time period but the number of antimicrobial resistant isolates did increase (8% vs 1%, p = 0.04). The greatest risk factors for PLA relative to general populations included current malignancy, liver-transplant, end-stage renal disease, and cirrhosis. Thirty-day mortality was 7.4% and independent risk factors included polymicrobial bacteremia, absence of abscess drainage, congestive-heart failure, a history of liver disease, and admission bilirubin. CONCLUSIONS: Pyogenic liver abscess is a health concern with rising incidence rate. The increasing prevalence of comorbidities in our population and factors that are associated with risk of PLA suggests this will continue to be an emerging diagnosis of concern. Increasing prevalence of antibiotic resistant organisms compounding unclear optimal treatment regimens is an issue that requires urgent study.

Applications of artificial intelligence in pancreatic and biliary diseases.

The application of artificial intelligence (AI) in medicine has increased rapidly with respect to tasks including disease detection/diagnosis, risk stratification, and prognosis prediction. With recent advances in computing power and algorithms, AI has shown promise in taking advantage of vast electronic health data and imaging studies to supplement clinicians. Machine learning and deep learning are the most widely used AI methodologies for medical research and have been applied in pancreatobiliary diseases for which diagnosis and treatment selection are often complicated and require joint consideration of data from multiple sources. The aim of this review is to provide a concise introduction of the major AI methodologies and the current landscape of AI research in pancreatobiliary diseases.

Endoscopic and percutaneous biliary interventions in patients with altered upper gastrointestinal anatomy-the Munich Multicenter Experience.

BACKGROUND: In patients with altered upper gastrointestinal anatomy, conventional endoscopic retrograde cholangiography is often not possible and different techniques, like enteroscopy-assisted or percutaneous approaches are required. Aim of this study was to analyze success and complication rates of these techniques in a large collective of patients in the daily clinical practice in a pre-endosonographic biliary drainage era. PATIENTS AND METHODS: Patients with altered upper gastrointestinal anatomy with biliary interventions between March 1st, 2006, and June 30th, 2014 in four tertiary endoscopic centers in Munich, Germany were retrospectively analyzed. RESULTS: At least one endoscopic-assisted biliary intervention was successful in 234/411 patients (56.9%)-in 192 patients in the first, in 34 patients in the second and in 8 patients in the third attempt. Success rates for Billroth-II/Whipple-/Roux-en-Y reconstruction were 70.5%/56.7%/49.5%. Complication rates for these reconstructions were 9.3%/6.5%/6.3%, the overall complication rate was 7.1%. Success rates were highest in patients with Billroth-II reconstruction where use of a duodenoscope was possible, complication rates were also highest in this scenario. Success rates were lowest in longer-limb anatomy like Roux-en-Y reconstruction. Percutaneous biliary drainages (PTBD) were inserted 268 times with substantially higher success (90.7%) as well as complication rates (11.6%) compared to the endoscopic approach. Compared to patients treated endoscopically, patients with PTBD had a lower performance status, more severe cholestasis and a significant higher rate of malignant underlying disease. CONCLUSION: In patients with altered upper gastrointestinal anatomy, success rates of endoscopic-assisted biliary interventions are lower compared to PTBD. Still, due to the beneficial complication rates of the endoscopic approach, this technique should be preferred whenever possible and in selected patients who still need to be defined in detail, repeated endoscopic attempts are useful to help achieve the desired result.

A 3-Year MBSAQIP propensity-matched analysis of Roux-en-Y gastric bypass with concomitant cholecystectomy: Is the robotic or laparoscopic approach preferred?

BACKGROUND: The primary objective of this study was to compare outcomes of patients undergoing minimally invasive RYGB (MIS/RYGB) versus MIS/RYGB with concomitant Cholecystectomy (CCY). A secondary objective was to compare the outcomes for laparoscopic RYGB (LRYGB) and robotic RYGB (RRYGB) with concomitant CCY. METHODS: Outcomes of 117,939 MIS/RYGB with and without CCY were propensity-matched (Age, Gender, BMI, Comorbidities), 10:1, using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database from 2015-2017. The MIS/RYGB with CCY were then separated into LRYGB and RRYGB cases for comparison. Exclusion criteria included emergency cases, conversions to open, and age less than 18. RESULTS: The operative time and length of stay (LOS) was significantly increased with addition of concomitant CCY. There was no significant difference in readmission, reoperation, intervention, morbidity, or mortality. The RRYGB with CCY approach was associated with a significantly longer operative times compared to the LRYGB with CCY (177 vs. 135 min, p < 0.0001). The laparoscopic and robotic groups demonstrated no significant difference LOS, readmission, reoperation, intervention, morbidity, or mortality rates. CONCLUSIONS: Our study demonstrates that concomitant cholecystectomy increased the operative time and length of stay. However, concomitant CCY was not associated with any increased morbidity. The study demonstrated no significant difference in morbidity between robotic and laparoscopic approach. The robotic approach, however, was associated with a significantly longer operative time compared to the laparoscopic approach. While the indications for CCY remain controversial, concomitant CCY does not convey additional risk regardless of operative approach.

Quantitative MRCP Imaging: Accuracy, Repeatability, Reproducibility, and Cohort-Derived Normative Ranges.

BACKGROUND: Magnetic resonance cholangiopancreatography (MRCP) is an important tool for noninvasive imaging of biliary disease, however, its assessment is currently subjective, resulting in the need for objective biomarkers. PURPOSE: To investigate the accuracy, scan/rescan repeatability, and cross-scanner reproducibility of a novel quantitative MRCP tool on phantoms and in vivo. Additionally, to report normative ranges derived from the healthy cohort for duct measurements and tree-level summary metrics. STUDY TYPE: Prospective. PHANTOMS/SUBJECTS: Phantoms: two bespoke designs, one with varying tube-width, curvature, and orientation, and one exhibiting a complex structure based on a real biliary tree. Subjects Twenty healthy volunteers, 10 patients with biliary disease, and 10 with nonbiliary liver disease. SEQUENCE/FIELD STRENGTH: MRCP data were acquired using heavily T2 -weighted 3D multishot fast/turbo spin echo acquisitions at 1.5T and 3T. ASSESSMENT: Digital instances of the phantoms were synthesized with varying resolution and signal-to-noise ratio. Physical 3D-printed phantoms were scanned across six scanners (two field strengths for each of three manufacturers). Human subjects were imaged on four scanners (two fieldstrengths for each of two manufacturers). STATISTICAL TESTS: Bland-Altman analysis and repeatability coefficient (RC). RESULTS: Accuracy of the diameter measurement approximated the scanning resolution, with 95% limits of agreement (LoA) from -1.1 to 1.0 mm. Excellent phantom repeatability was observed, with LoA from -0.4 to 0.4 mm. Good reproducibility was observed across the six scanners for both phantoms, with a range of LoA from -1.1 to 0.5 mm. Inter- and intraobserver agreement was high. Quantitative MRCP detected strictures and dilatations in the phantom with 76.6% and 85.9% sensitivity and 100% specificity in both. Patients and healthy volunteers exhibited significant differences in metrics including common bile duct (CBD) maximum diameter (7.6 mm vs. 5.2 mm P = 0.002), and overall biliary tree volume 12.36 mL vs. 4.61 mL, P = 0.0026). DATA CONCLUSION: The results indicate that quantitative MRCP provides accurate, repeatable, and reproducible measurements capable of objectively assessing cholangiopathic change. Evidence Level: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:807-820.

Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis, IAC) and pancreas (autoimmune pancreatitis, AIP). We recently identified highly expanded IgG4+ B-cell receptor clones in blood and affected tissues of patients with IAC/AIP suggestive of specific (auto)antigenic stimuli involved in initiating and/or maintaining the inflammatory response. This study aimed to identify (auto)antigen(s) that are responsible for the clonal expansion of IgG4+ B cells in IgG4-RD. DESIGN: We screened sera of patients with IAC/AIP (n=50), in comparison to control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies (n=47), for reactivity against human H69 cholangiocyte lysates on immunoblot. Subsequently, target antigens were immunoprecipitated and analysed by mass spectrometry. RESULTS: Prominent reactivity against a 56 kDa protein was detected in human H69 cholangiocyte lysates exposed to sera of nine patients with IAC/AIP. Affinity purification and mass spectrometry analysis identified annexin A11, a calcium-dependent phospholipid-binding protein. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD of the biliary tract/pancreas/salivary glands and not in disease mimickers with PSC and pancreatobiliary malignancies. Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. CONCLUSION: Our data suggest that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. METHODS: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. RESULTS: A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro. CONCLUSIONS: These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. LAY SUMMARY: Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.

Cholangioscopy Is Safe and Feasible in Elderly Patients.

BACKGROUND & AIMS: Although cholangioscopy is widely used during endoscopic retrograde cholangiopancreatiography (ERCP), its safety and feasibility for elderly patients are not well established. We aimed to evaluate the safety and feasibility of cholangioscopy in elderly patients. METHODS: We performed a retrospective study of all ERCPs with single-operator cholangioscopy (SOC) performed at 3 tertiary referral hospitals from March 2012 through October 2015. We collected data on patient demographics, procedure indications, findings, complications, and success rates (complete success was achieved if all intended diagnostic and therapeutic procedures were performed, such as tissue sample collection or complete removal of stones). The cohort was divided into 3 groups: patients younger than 65 years (group 1, n = 178), patients 65-75 years old (group 2, n = 86), and patients older than 75 years (group 3, n = 77). We used 1-way ANOVA, the χ2 test, and the Wilcoxon sum rank test to compare study variables. The primary aim was to assess rates of complications from ERCP with SOC in elderly patients compared with younger patients. RESULTS: Baseline clinical features were similar among groups, except for a higher prevalence of co-morbidities in group 3. The indication for and findings from ERCP with SOC differed among the groups; stricture or tumor was the most common indication in groups 1 and 3-the most common findings were strictures and masses, respectively. In group 2, choledocholithiasis was the most common indication and finding. The success rate, analyzed in a subset of 209 patients, was 88.5% overall and did not differ significantly among groups. The overall rate of complication was 7.33% with no significant difference among groups (7.30% for group 1, 6.98% for group 2, and 7.79% for group 3) (P < .17). CONCLUSIONS: In a retrospective analysis of ERCPs with SOCs, we found this procedure to be safe for elderly patients (older than 75 years), who had rates of complications and hospital admission similar to those of younger patients.

Intrahepatic bile duct primary cilia in biliary atresia.

AIM: The etiopathogenesis of non-syndromic biliary atresia (BA) is obscure. The primary aim was to investigate intrahepatic bile duct cilia (IHBC) in BA at diagnosis and its correlation with clinical outcome. The secondary aim was to analyze IHBC in routine paraffin-embedded liver biopsies using conventional scanning electron microscopy (SEM). METHODS: Surgical liver biopsies taken at diagnosis from 22 BA infants (age range, 39-116 days) and from eight children with non-BA chronic cholestasis (age range, 162 days -16.8 years) were evaluated for IHBC by immunofluorescence (IF) and SEM. A minimum 18-month follow-up after surgery was available for all patients. RESULTS: By IF, cilia were present in 6/8 (75%) non-BA but only in 3/22 (14%) BA cases, and cilia were reduced or absent in 19/22 (86%) BA and 2/8 (25%) non-BA livers (P < 0.01). In BA, cilia presence was found to be associated with clearance of jaundice at 6-month follow-up (P < 0.05). However, high overall survival rates with native liver, >90% at 12 months, and >70% at 24 months post-surgery, were recorded regardless of cilia presence/absence at diagnosis. Electron microscopy was able to detect bile ducts and cilia in routine liver biopsies, revealing significant abnormalities in 100% BA livers. CONCLUSIONS: The presence of IHBC in BA livers at the diagnosis was associated with resolution of cholestasis, although was not predictive of short-term survival with native liver. Scanning electron microscopy represents a powerful new tool to study routine liver biopsies in biliary disorders. Cilia dysfunction in BA pathogenesis and/or disease progression warrants further investigation.

Utility of common bile duct measurement in ED point of care ultrasound: A prospective study.

BACKGROUND: Measurement of the common bile duct (CBD) is considered a fundamental component of biliary point-of-care ultrasound (POCUS), but can be technically challenging. OBJECTIVE: The primary objective of this study was to determine whether CBD diameter contributes to the diagnosis of complicated biliary pathology in emergency department (ED) patients with normal laboratory values and no abnormal biliary POCUS findings aside from cholelithiasis. METHODS: We performed a prospective, observational study of adult ED patients undergoing POCUS of the right upper quadrant (RUQ) and serum laboratory studies for suspected biliary pathology. The primary outcome was complicated biliary pathology occurring in the setting of normal laboratory values and a POCUS demonstrating the absence of gallbladder wall thickening (GWT), pericholecystic fluid (PCF) and sonographic Murphy's sign (SMS). The association between CBD dilation and complicated biliary pathology was assessed using logistic regression to control for other factors, including laboratory findings, cholelithiasis and other sonographic abnormalities. RESULTS: A total of 158 patients were included in the study. 76 (48.1%) received non-biliary diagnoses and 82 (51.9%) were diagnosed with biliary pathology. Complicated biliary pathology was diagnosed in 39 patients. Sensitivity of CBD dilation for complicated biliary pathology was 23.7% and specificity was 77.9%. CONCLUSION: Of patients diagnosed with biliary pathology, none had isolated CBD dilatation. In the absence of abnormal laboratory values and GWT, PCF or SMS on POCUS, obtaining a CBD measurement is unlikely to contribute to the evaluation of this patient population.