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Objectives: To evaluate the prevalence and meaning of antineutrophil cytoplasmic antibodies (ANCA) positivity in a cohort of IgG4-related disease (IgG4-RD)., Methods: We identified patients with ANCA determination from a retrospective cohort of 69 patients with IgG4-RD. ANCA were measured by indirect immunofluorescence microscopy (IIF) and/or proteinase 3 (PR3)-ANCA and MPO-ANCA by ELISA. IIF patterns were classified as perinuclear (P-ANCA), cytoplasmic (C-ANCA) and atypical (X-ANCA). We compared the ANCA-positive vs the ANCA-negative IgG4-RD group., Results: Out of 69 patients, 31 IgG4-RD patients had an ANCA determination. Four patients with concomitant systemic autoimmune diseases were excluded. We found positive ANCA by IIF in 14 (56%) of 25 patients tested. The most common IIF pattern was C-ANCA in eight (57.1%), followed by dual C-ANCA/X-ANCA in four (28.6%) and P-ANCA and dual C-ANCA/P-ANCA in one each (7.1%). Of the 20 patients with ANCA determination by both IIF and ELISA, four have positive ANCA by ELISA (three for MPO-ANCA and one for PR3-ANCA). Of the two patients with only ELISA determination, one was positive for MPO-ANCA. The prevalence of ANCA positivity by ELISA was 22.7% (5 out of 22 patients). ANCA was more frequent in the Mikulizc/systemic phenotype (42.9%) compared with other phenotypes (P = 0.04). ANCA-positive IgG4-RD patients had more frequently lymph node and kidney involvement, high IgG1 levels and erythrocyte sedimentation rate, and positive antinuclear antibodies., Conclusion: ANCA are found in a significant number of patients with IgG4-RD and differed from the ANCA-negative group in terms of clinical and serological features., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Identifying an infection may be difficult in the ED. Neutrophilic leukocytosis is often used in the diagnosis of infection despite its lack of specificity in situations of stress. Our objective was to study the value of each parameter of the WBC count, in particular eosinopenia, to diagnose bacterial infections in the ED. We conducted a retrospective and observational study over a period of 6 months. All patients with one of the following diagnoses were eligible: pneumonia (9.9%), pyelonephritis (26.2%), prostatitis (8.4%), appendicitis (26.2%), cholecystitis (8.4%), and diverticular sigmoiditis (5%). A total of 466 infected patients were included for statistical analysis, and a control group of 466 uninfected patients was randomly selected in the same period of time. All leukocyte count parameters were significantly modified (p < 0.001) in the infected group compared with the control group. Neutrophils and total leukocytes remain the two most suitable parameters for the diagnosis of infections in the ED. Eosinopenia represented the most efficient parameter of the WBC count for the diagnosis of urinary and biliary tract infections. Deep eosinopenia presented a specificity of 94% for the diagnosis of infection. Any modification of the WBC count associated with an elevation of CRP (> 40 mg/L) or fever (> 38.5 °C) showed a high specificity for the diagnosis of infection. A careful analysis of the WBC count remains a valuable tool for the diagnosis of infection in the ED.

The liver is a vital organ with distinctive anatomy, histology and heterogeneous cell populations. These characteristics are of particular importance in maintaining immune homeostasis within the liver microenvironments, notably the biliary tree. Cholangiocytes are the first line of defense of the biliary tree against foreign substances, and are equipped to participate through various immunological pathways. Indeed, cholangiocytes protect against pathogens by TLRs-related signaling; maintain tolerance by expression of IRAK-M and PPARγ; limit immune response by inducing apoptosis of leukocytes; present antigen by expressing human leukocyte antigen molecules and costimulatory molecules; recruit leukocytes to the target site by expressing cytokines and chemokines. However, breach of tolerance in the biliary tree results in various cholangiopathies, exemplified by primary biliary cholangitis, primary sclerosing cholangitis and biliary atresia. Lessons learned from immune tolerance of the biliary tree will provide the basis for the development of effective therapeutic approaches against autoimmune biliary tract diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study aimed to elucidate the impact of epithelial regenerative responses and immune cell infiltration on biliary complications after liver transplantation. Bile duct (BD) damage after cold storage was quantified by a BD damage score and correlated with patient outcome in 41 patients. Bacterial infiltration was determined by fluorescence in situ hybridization (FISH). BD samples were analyzed by immunohistochemistry for E-cadherin, cytokeratin, CD56, CD14, CD4, CD8, and double-immunofluorescence for cytokine production and by messenger RNA (mRNA) microarray. Increased mRNA levels of adherens junctions (P < 0.01) were detected in damaged BDs from patients without complications compared with damaged BDs from patients with biliary complications. Immunohistochemistry showed increased expression of E-cadherin and cytokeratin in BDs without biliary complications (P = 0.03; P = 0.047). FISH analysis demonstrated translocation of bacteria in BDs. However, mRNA analysis suggested an enhanced immune response in BDs without biliary complications (P < 0.01). Regarding immune cell infiltration, CD4 + and CD8 + cells were significantly increased in patients without complications compared with those with complications (P = 0.02; P = 0.01). In conclusion, following BD damage during cold storage, we hypothesize that the functional regenerative capacity of biliary epithelium and enhanced local adaptive immune cell infiltration are crucial for BD recovery. Such molecular immunological BD analyses therefore could help to predict biliary complications in cases of "major" epithelial damage after cold storage.Liver Transplantation 23 1422-1432 2017 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Aim: To evaluate the differences in outcomes between ABO-incompatible (ABO-I) liver transplantation (LT) and ABO-compatible (ABO-C) LT., Methods: A systematic review and meta-analysis were performed by searching eligible articles published before No-vember 28, 2016 on MEDLINE (PubMed), EMBASE, and Cochrane databases. The primary endpoints were graft survival, patient survival, and ABO-I-related complications., Results: Twenty-one retrospective observational studies with a total of 8247 patients were included in this meta-analysis. Pooled results of patient survival for ABO-I LT were comparable to those for ABO-C LT. However, ABO-I LT showed a poorer graft survival than ABO-C LT (1-year: OR = 0.66, 95%CI: 0.57-0.76, P < 0.001; 3-year: OR = 0.74, 95% CI 0.64-0.85, P < 0.001; 5-yearr: OR =0.75, 95%CI: 0.66-0.86, P < 0.001). Furthermore, ABO-I LT was associated with more incidences of antibody-mediated rejection (OR = 74.21, 95%CI: 16.32- 337.45, P < 0.001), chronic rejection (OR =2.28, 95%CI: 1.00-5.22, P = 0.05), cytomegalovirus infection (OR = 2.64, 95%CI: 1.63-4.29, P < 0.001), overall biliary complication (OR = 1.52, 95%CI: 1.01-2.28, P = 0.04), and hepatic artery complication (OR = 4.17, 95%CI: 2.26-7.67, P < 0.001) than ABO-C LT. In subgroup analyses, ABO-I LT and ABO-C LT showed a comparable graft survival in pediatric patients and those using rituximab, and ABO-I LT showed an increased acute cellular rejection in cases involving deceased donor grafts., Conclusion: Although patient survival in ABO-I LT was comparable to that in ABO-C LT, ABO-I LT was inferior to ABO-C LT in graft survival and several complications. Graft survival of ABO-I LT could be comparable to that of ABO-C LT in pediatric patients and those using rituximab., Competing Interests: Conflict-of-interest statement: No conflicts of interest were declared for all authors.

IgG4-related hepatobiliary diseases are part of a multiorgan fibroinflammatory condition termed IgG4-related disease, and include IgG4-related sclerosing cholangitis (IgG4-SC) and IgG4-related hepatopathy. These diseases can present with biliary strictures and/or mass lesions, making them difficult to differentiate from primary sclerosing cholangitis (PSC) or other hepatobiliary malignancies. Diagnosis is based on a combination of clinical, biochemical, radiological and histological findings. However, a gold standard diagnostic test is lacking, warranting the identification of more specific disease markers. Novel assays - such as the serum IgG4:IgG1 ratio and IgG4:IgG RNA ratio (which distinguish IgG4-SC from PSC with high serum IgG4 levels), and plasmablast expansion to recognize IgG4-SC with normal serum IgG4 levels - require further validation. Steroids and other immunosuppressive therapies can lead to clinical and radiological improvement when given in the inflammatory phase of the disease, but evidence for the efficacy of treatment regimens is limited. Progressive fibrosclerotic disease, liver cirrhosis and an increased risk of malignancy are now recognized outcomes. Insights into the genetic and immunological features of the disease have increased over the past decade, with an emphasis on HLAs, T cells, circulating memory B cells and plasmablasts, chemokine-mediated trafficking, as well as the role of the innate immune system.

Increasing evidence points to the contribution of the intestinal microbiome as a potentially key determinant in the initiation and/or progression of hepatobiliary disease. While current understanding of this dynamic is incomplete, exciting insights are continually being made and more are expected given the developments in molecular and high-throughput omics techniques. In this brief review, we provide a practical and updated synopsis of the interaction of the intestinal microbiome with the liver and its downstream impact on the initiation, progression and complications of hepatobiliary disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context: Immunoglobulin G4 (IgG4)-related disease is a systemic fibroinflammatory disease capable of affecting virtually any organ. Although the pancreas and hepatobiliary system are commonly affected, involvement of the tubular gut is unusual. The pancreatic manifestations of this disease (autoimmune pancreatitis) often mimic pancreatic carcinoma, whereas the hepatobiliary manifestations are mistaken for cholangiocarcinoma or primary sclerosing cholangitis. The characteristic histologic features include a dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis. An increase in IgG4(+) plasma cells and an IgG4 to IgG ratio of more than 40% are considered obligatory components of the diagnostic algorithm., Objective: To review the challenges associated with the diagnosis of IgG4-related disease of the gastrointestinal tract., Data Sources: A review of pertinent literature, along with the author's personal experience, based on institutional and consultation materials., Conclusion: The complete spectrum of histologic changes is seldom captured in a biopsy specimen, and thus, the histopathology findings are best interpreted within the overall clinical context. Increased IgG4(+) plasma cells are identified in a variety of benign and malignant diseases of the gastrointestinal tract.

It is ironic that the liver, which serves a critical function in immune tolerance, itself becomes the victim of an autoimmune attack. Indeed, liver autoimmunity and the autoimmune diseases associated with both innate and adaptive responses to hepatocytes and/or cholangiocytes are models of human autoimmunity. For example, in primary biliary cirrhosis, there exists a well-defined and characteristic autoantibody and considerable homogeneity between patients. In autoimmune hepatitis, there are clinical characteristics that allow a rigorous subset definition and well-defined inflammatory infiltrates. In both cases, there are defects in a variety of immune pathways and including regulatory cells. In primary sclerosing cholangitis, with its characteristic overlap with inflammatory bowel disease, there are unique defects in innate immunity and particular important contribution of lymphoid homing to disease pathogenesis. In these diseases, as with other human autoimmune processes, there is the critical understanding that pathogenesis requires a genetic background, but is determined by environmental features, and indeed the concordance of these diseases in identical twins highlights the stochastic nature of immunopathology. Unfortunately, despite major advances in basic immunology and in immunopathology in these diseases, there remains a major void in therapy. The newer biologics that are so widely used in rheumatology, neurology, and gastroenterology have not yet seen success in autoimmune liver disease. Future efforts will depend on more rigorous molecular biology and systems analysis in order for successful application to be made to patients.

Objectives: Although most reported patients with immunoglobulin G4-related disease (IgG4-RD) are from the Far East, we aimed to identify patients suffering from IgG4-RD in our University Centre in Debrecen, Hungary., Method: Serum IgG4 levels were measured at 51 of our 800 patients followed up because of Sjögren's syndrome (SS) if one or more clinical signs during the disease course raised the possibility of IgG4-RD (persisting salivary gland swelling, absence of anti-Ro/SSA and anti-La/SSB antibodies in the serum, and positive salivary gland biopsy, coexistence of autoimmune pancreatitis, autoimmune hepatitis, or primary sclerosing cholangitis, persisting lymphadenopathy). Where available, histological samples of small salivary gland biopsies were revised to detect the particular features of IgG4-RD. Pathologists and surgeons were informed about the disease and asked to refer suspicious cases., Results: Based on our survey, eight patients were identified with IgG4-RD. Pancreatic, salivary gland, aortic, and retroperitoneal manifestations were detected. Of the 51 patients with SS, four appeared to have IgG4-RD, but eventually one was excluded., Conclusions: Although IgG4-RD is not yet well known to physicians of Western countries, it occurs in Caucasians and probably in other races as well. Moreover, our eight cases diagnosed with IgG4-RD demonstrate a relatively large European patient population collected in a single centre. European clinicians, and especially rheumatologists, should be informed and at least certain laboratories should be prepared to investigate patient samples if the suspicion of IgG4-RD is raised. The main clinical significance of an accurate diagnosis is the extreme corticosteroid sensitivity of IgG4-RD.

Aim: To investigate the pathogenesis of biliary casts after liver transplantation relative to their morphology and biochemical markers., Methods: The microstructure of biliary casts was assessed using scanning electron microscopy and Hematoxylin and eosin staining assessed their histology. The expression levels of CD3, CD5, CD34, CD68 and CD79a in these biliary casts were evaluated immunohistochemically., Results: Biliary casts differed widely in their microstructure, with some containing blood vessels positive for CD34 and collagen fibers with positive Masson staining. Large numbers of neutrophils and other inflammatory cells were present, but only on the edge of the biliary casts; although the boundaries were clear without crossover. None of the biliary casts contained T-lymphocytes, B-lymphocytes, macrophages and other inflammatory cells., Conclusion: The microcostructure of biliary casts differed. Bacteria and acute rejection are not clearly related to their formation.

Cholangiocytes, or bile duct epithelia, were once thought to be the simple lining of the conduit system comprising the intra- and extrahepatic bile ducts. Growing experimental evidence demonstrated that cholangiocytes are in fact the first line of defense of the biliary system against foreign substances. Experimental advances in recent years have unveiled previously unknown roles of cholangiocytes in both innate and adaptive immune responses. Cholangiocytes can release inflammatory modulators in a regulated fashion. Moreover, they express specialized pattern-recognizing molecules that identify microbial components and activate intracellular signaling cascades leading to a variety of downstream responses. The cytokines secreted by cholangiocytes, in conjunction with the adhesion molecules expressed on their surface, play a role in recruitment, localization, and modulation of immune responses in the liver and biliary tract. Cholangiocyte survival and function is further modulated by cytokines and inflammatory mediators secreted by immune cells and cholangiocytes themselves. Because cholangiocytes act as professional APCs via expression of major histocompatibility complex antigens and secrete antimicrobial peptides in bile, their role in response to biliary infection is critical. Finally, because cholangiocytes release mediators critical to myofibroblastic differentiation of portal fibroblasts and hepatic stellate cells, cholangiocytes may be essential in the pathogenesis of biliary cirrhosis.

Opisthorchiasis caused by Opisthorchis viverrini infection induces hepatobiliary disease (HBD)-associated cholangiocarcinoma (CCA) via a chronic inflammatory immune response. Here, we evaluated specific IgG and IgA antibodies against different fractions of O. viverrini antigen in residents from an endemic community in Northeast Thailand with varying hepatobiliary abnormalities. Crude somatic O. viverrini antigen was purified into three fractions (viz., P1, P2 and P3) by gel infiltration chromatography and these served as antigens for detection of fluke-specific IgG and IgA antibodies by enzyme-linked immunosorbent assay (ELISA). The results revealed fluke-specific IgG and IgA antibody levels-against these antigens from subjects with O. viverrini-positive HBD-higher than in subjects with O. viverrini-negative HBD. Interestingly, the rank of fluke-specific IgG (and not IgA) antibody levels against crude extract and P1 antigens was CCA>severe HBD>mild HBD>healthy individuals. Purified antigens reduced cross-reactivity with other parasites compared to the crude antigen. Multiple linear regression analysis showed that HBD status was significantly associated with the liver fluke-specific IgG antibody against purified antigens. These results suggest that purified O. viverrini-antigen improves serodiagnosis for the evaluation of opisthorchiasis-associated HBD, and may be useful in the screening of opisthorchiasis in subjects at risk of developing CCA., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Since the discovery of Helicobacter pylori, various enterohepatic Helicobacter spices have been detected in the guts of humans and animals. Some enterohepatic Helicobacters have been associated with inflammatory bowel disease or liver disease in mice. However the association of these bacteria with human diseases remains unknown., Materials and Methods: We collected 126 bile samples from patients with cholelithiasis, cholecystitis, gallbladder polyp, and other nonbiliary diseases. Samples were screened for the presence of enterohepatic Helicobacter spp. using cultures, nested PCR, or in situ hybridization. We tested for antibodies to H. pylori and H. hepaticus by Western blot analysis., Results: Attempts at cultivation were unsuccessful. However, H. hepaticus was detected in bile samples with nested PCR whereas H. bilis was not. Helicobacter hepaticus in the bile was confirmed by in situ hybridization, but H. hepaticus from bile samples was coccoid in appearance. We detected immunoglobulin G antibodies to H. hepaticus in bile samples by Western blotting. Helicobacter hepaticus was detected in 40 (32%) of total 126 samples as H. hepaticus positive if at least one of the three methods with nested PCR, in situ, or Western blotting. Patients with cholelithiasis (41%) and cholecystitis with gastric cancer (36%) had significantly higher (p = .029) prevalence of H. hepaticus infection than samples from patients with other diseases., Conclusion: Helicobacter hepaticus may closely associate with diseases of the liver and biliary tract in humans.

Bile ducts lined with biliary epithelial cells, or cholangiocytes, are the main components of the biliary system in liver. Cholangiocytes participate in the production and transport of bile substances, as well as participate in immune responses. Cholangiocytes protect against pathogens by expressing toll-like receptors and anti-microbial peptides; act as antigen-presenting cells by expressing human leukocyte antigen molecules and costimulatory molecules; recruit leukocytes to the target site by expressing adhesion molecules, cytokines, and chemokines; and induce apoptosis of leukocytes to limit the immune responses. Several cholangiopathies result from dysfunctions of the biliary system. They can broadly be divided into autoimmune, genetic, infectious, drug, and ischemic-injury-induced categories. The pathogenesis of many of these cholangiopathies is unclear and treatment is limited. Further understanding of the complexity of the biliary system is critical for medical advancements in this field.

Whereas autoimmune pancreatitis is an established entity characterized by high serum concentrations of IgG4, IgG4 cholangitis is a quite new entity characterized by a massive infiltration of bile ducts by IgG4 positive lymphoplasmocytic cells. IgG4 cholangitis should therefore be differentiated from primary sclerosing cholangitis based on clinics, radiological and biological markers. This paper is aimed at reviewing all new aspects of diseases associated with high levels of IgG4.

Purpose of Review: Publications concerning liver histopathology in fatty liver disease and chronic hepatitis C, iron and copper overload, and liver transplantation from the past year have been surveyed to highlight useful concepts and diagnostic information., Recent Findings: Two microscopic forms of pediatric nonalcoholic steatohepatitis have been described: type 1 in which hepatocyte ballooning and/or pericellular fibrosis accompany the steatosis; and type 2 which has portal tract inflammation and/or fibrosis as the salient accompanying feature. In chronic hepatitis C, the ductular reaction appears to be a major factor associated with fibrosis. In patients transplanted for hepatitis C virus-related cirrhosis, immunostaining of post-transplant liver biopsies for alpha-smooth muscle actin (i.e. in activated hepatic stellate cells) may identify those individuals at risk for severe recurrence. Clinicopathological papers on several forms of non-HFE hemochromatosis were published and Wilson's disease was described in individuals of 60 years or more in age. Cholestasis in childhood was expertly reviewed and histopathologic precursor lesions of hepatocellular carcinoma were also examined in a comprehensive article., Summary: Recent publications with impact on liver biopsy interpretation include a morphologic classification of nonalcoholic steatohepatitis in childhood, the differential diagnosis of childhood cholestasis and pathogenetic factors involved in fibrogenesis in chronic hepatitis C.

Background: Enteric Helicobacter species might be a risk factor for chronic liver and biliary tract diseases., Aims: To analyse serum antibody levels to three enteric Helicobacter species in patients with various biliary tract and chronic liver diseases and compare results with corresponding parameters for an adult population group, known to have a high prevalence of Helicobacter pylori infection, and with healthy blood donors, to explore a possible association of enteric Helicobacter with chronic liver diseases., Subjects: Sera of 90 patients with various chronic liver diseases, 121 Estonian adult persons and 68 blood donors were analysed., Methods: Sera, previously tested for H. pylori were analysed for IgG to Helicobacter hepaticus, Helicobacter bilis and Helicobacter pullorum. ELISA was initially used for screening and exclusion of negative cases. Sera with positive ELISA results were further analysed by immunoblot. To remove cross-reactive antibodies between H. pylori and the enteric species, sera were pre-absorbed with lysed H. pylori cells., Results: Liver patients showed a significantly higher seroprevalence to H. hepaticus and H. bilis, compared with the adult population group (p=0.0001 and 0.04, respectively), and to H. hepaticus, compared with blood donors (p=0.01). Patients with autoimmune hepatitis showed no significant antibody reactivity to the enteric Helicobacter spp. in contrast to patients with other chronic liver diseases., Conclusion: Patients with chronic liver diseases, except autoimmune hepatitis patients, showed increased antibody levels to H. bilis/H. hepaticus compared with the population and blood donors indicating a possible role of enteric Helicobacter in the natural course of chronic liver diseases. Immunoblot seems to be a promising method for serodiagnosis of infections with these fastidious pathogens.

Autoimmune hepatobiliary diseases AIHBD comprise autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and the overlap syndromes. Early diagnosis and treatment of AIHBD are essential for the prevention of the high morbidity, and mortality, that is, otherwise, associated with untreated patients. Screening for AIHBD relies heavily on the use of serological tests for the detection of serum autoantibodies that associate with the diseases. Understanding these tests, and the results produced, is important for the efficient diagnosis/exclusion of these diseases. In this review, we discuss the various tests available in the clinical immunology laboratory for screening of AIHBD and comment on the significance of the results produced by each test. We hope that this review will highlight this group of autoimmune diseases and lead to more efficient and earlier diagnosis, and treatment, of patients with AIHBD.

Objectives: Autoimmune pancreatitis (AIP) is a unique clinical entity that has been recently proposed, and it is frequently associated with bile duct stricture. The aim of this study was to investigate the pathophysiology of the biliary tract involvement in patients with AIP., Methods: We evaluated the clinicopathologic findings in 16 patients with AIP. Surgical resection was performed in 7 of the patients because of suspicion of a pancreatic tumor; 8 of the other patients were treated with oral prednisolone (PSL) therapy, and the remaining patient was observed clinically and not treated. The pancreas, bile duct, and gallbladder in the surgical cases were examined histologically and immunohistochemically. We also assessed the clinical manifestations and diagnostic imaging findings before and after oral PSL therapy in the 8 patients treated with PSL., Results: Stricture of the extrahepatic bile duct was detected in 88% (14/16) of the patients. Thickening of the bile duct wall was detected in 94% (15/16), and thickening of the gallbladder wall was observed in 56% (9/16). Histologically, the bile duct and gallbladder wall were characterized by diffuse lymphoplasmacytic infiltration and marked interstitial fibrosis. Immunohistochemically, the diffusely infiltrating cells consisted of predominantly CD8- or CD4-positive T lymphocytes and IgG4-positive plasma cells. These findings were the same as in the inflammatory process that was observed in the pancreas. After oral PSL therapy, the pancreatic enlargement and irregular narrowing of the main pancreatic duct improved to almost their normal size in all 8 patients; however, stricture of the extrahepatic bile duct persisted in 4 of the patients (57%, 4/7) in whom it was detected before PSL therapy., Conclusions: Based on the pathophysiologic and histologic findings and the response to PSL therapy, the biliary involvement in AIP developed by the same mechanism as the pancreatitis. CD8- and CD4-positive lymphocytes and IgG4-positive plasma cells may play an important role in the pathogenesis of AIP.

Ischemic-type biliary lesions are a major complication following orthotopic liver transplantation. They occur in up to 26% of liver transplant recipients. Among other factors, unknown immunologic factors have always been assumed to be partly responsible for these lesions. CC-chemokines and their receptors play a key role in postoperative immunomodulation after liver transplantation. The non-function CC-chemokine receptor 5delta32 polymorphism (CCR5delta32) has been shown to lead to a lower rate of acute rejection after kidney transplantation; in liver transplantation the role of CCR5delta32 is unclear. We investigated the influence of the CCR5delta32 after liver transplantation with special regard to ischemic-type biliary lesions. The CC-chemokine receptor-5 (CCR5) of 146 recipients was analyzed by polymerase chain reaction to detect CCR5delta32 in blood samples of patients after liver transplantation. One hundred twenty patients with wild-type CCR5 and 26 patients with CCR5delta32 (1 homozygote, 25 heterozygote) were identified. Ischemic-type biliary lesions occurred in 14 of 120 patients with wild-type CCR5 and in 8 of 26 patients with CCR5delta32 polymorphism (P = = 0.01). 5 year patient survival with CCR5delta32 and CCR5 was 70% and 85%, respectively (P =.0067). Our results show that the CCR5delta32 is a significant risk factor for the development of ischemic-type biliary lesions after liver transplantation and leads to a reduction in 5-year survival. In conclusion, the CCR5 status should be screened prospectively before liver transplantation.

Background/aims: The value of serum tumor markers carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) in the differential diagnosis of obstructive biliary disease is dubious. We aimed to define their usefulness prospectively., Methods: Thirty-seven consecutive patients (12 female, 25 male, median age: 54, range: 19-83 years) who were referred for endoscopic retrograde cholanugiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) examination for obstructive jaundice were included (all with dilatation of biliary tree in ultrasonography or computerised tomography). Bile was obtained through the nasobiliary or external drainage catheter, placed with ERCP or PTC, respectively. Serum samples were taken from all patients at the time of acquisition of bile. Serum and bile samples were stored at -50 oC until they were tested. CA19-9 and CEA levels were measured with chemiluminescent enzyme immunoassay methods in serum and bile samples by using immulite GI-MA and CEA commercial kits, respectively (DPC(r), Los Angeles)., Results: In 22 patients with malignant disease, serum CEA levels were 38.6+/-115.8 ng/ml and CA19-9 were 386.9+/-409.7 U/ml, while in 15 patients with benign disease the serum CEA levels were 1.8+/-1.6 ng/ml and CA19-9 were 128.9+/-302.2 U/ml. The difference for both values was significant (p<0.05). In malignant disease bile CEA and CA19-9 levels were 160.8+/-457.8 ng/ml, 14000.9+/-19798 U/ml respectively, while in benign disease the corresponding levels were 21.08+/-48.6 ng/ml for CEA and 14818.9+/-24665.7 U/ml for CA19-9. The differences were not significant in this case (p>0.05)., Conclusion: It was concluded that serum CA19-9 levels are increased both in malignant and benign obstructive biliary diseases, albeit more significantly in the former. However, increase in serum CEA is mostly restricted to malignant diseases. Measurement of these markers in bile is of no value.

Murine extrahepatic bile duct epithelial cells (MEBEC) were isolated from extrahepatic bile ducts of BALB/c mice and established in primary culture. The epithelial origin was confirmed by positive cytokeratin 19 staining for these cells and the presence of microvilli and tight junctions under electron microscopy. By immunofluorescent staining with monoclonal antibodies and flow-cytometric analysis, MEBEC in culture constitutively express low levels of intercellular adhesion molecule (ICAM)-1, class I and class II major histocompatibility (MHC) antigens. The expression of ICAM-1 was significantly increased by interferon gamma (INF-gamma) or tumour necrosis factor alpha (TNF-alpha) stimulation. Class I and class II antigen expression were significantly enhanced by INF-gamma and in vitro murine cytomegalovirus (MCMV) infection. MEBEC infected with MCMV revealed a progressive cytopathic effect. MEBEC activated by INF-gamma or infected by MCMV induced a low but significant proliferation of allogeneic T cells and displayed a significant decrease in the absorbance at O.D. 550 nm in a microtitre tetrazolium assay after these treated cells were co-cultured with allogeneic T cells. These results suggest that following the up-regulation of surface MHC antigen and adhesion molecule expression with cytokines or MCMV, the MEBEC can function as antigen-presenting cells and initiate T-cell proliferation, which in turn trigger the recognition of MEBEC by effector T-cell-mediated cytotoxic responses. These findings may be implicated in the pathogenesis of virally induced, immune-mediated extrahepatic bile duct damage disorders.

Currently available evidence is insufficient to classify PBC and AIC as separate diseases. The ultimate answer to the question of whether AIC, defined as AMA-negative PBC with ANA or SMA, is a disease distinct from AMA-positive PBC with or without ANA will require a detailed comparison of etiologic factors and pathogenetic mechanisms, once they are elucidated. It is intriguing to consider the suggestion of Heathcote that the term autoimmune cholangitis be adopted to describe PBC with or without detectable AMA. However, it is improbable that the venerable term PBC will be supplanted. Hepatologists will probably continue to use the terms AIC and AMA-negative PBC interchangeably, with little risk of being misunderstood.

An autosomal recessive murine mutation, coined "aly/aly" or "alymphoplasia," was recently reported. Homozygotes for aly are defective in both humoral and cell-mediated immune function and have diffuse lymphoid cell infiltration of various tissues, particularly around the conduit ducts of the pancreas and salivary glands. In pilot studies in our laboratories, aly/aly mice were found to have peculiar biliary tract lesions, which were analyzed histologically and immunohistochemically in the present study. The livers of aly/aly mice older than 8 weeks consistently showed a variable lymphoid cell infiltration with lymph follicle formation in portal tracts; intrahepatic biliary epithelial cells showed various types of damage including pseudopyloric gland metaplasia and proliferative changes. In addition, the extrahepatic bile duct and intrahepatic large bile duct were found to contain an acidophilic substance in their epithelial cytoplasm. In the lumen and occasionally in the cytoplasm of these bile ducts, acidophilic crystals were also seen. Ultrastructurally, the intracytoplasmic acidophilic substances consisted of membrane-bound intracytoplasmic inclusions with homogeneous electron density, likely derived from rough endoplasmic reticulum (ER). Immunohistochemically, the cytoplasmic acidophilic substances were simultaneously positive for cystatin C, gastrin, serotonin, and somatostatin. In contrast, the acidophilic crystals did not react with any of these antibodies. These findings suggest that the intracytoplasmic acidophilic substances may contain a precursor of the peptide hormones, possibly because of defective secretion or intracellular transport. We believe that the aly/aly mouse is a useful model for the analysis of biliary metabolic events, and for studies of the interaction of the immune system and biliary destruction.

Background/aims: This study was designed to assess the correlation of interleukin 6 (IL-6) with jaundice reduction by percutaneous transhepatic cholangio-drainage (PTCD) for obstructive jaundice., Methodology: We measured serum and bile IL-6 concentrations by enzyme linked immuno-sorbent assay before and after PTCD in 26 patients with obstructive jaundice. The patients were divided into two groups according to their bilirubin decrease rate., Results: Serum IL-6 levels measured before and after PTCD in the slowly decreasing bilirubin group ("poor" group) were significantly higher than those of the rapidly decreasing bilirubin group ("good" group). Measures of bile IL-6 in the "poor" group remained high from 3 to 14 days after PTCD in comparison with the "good" group., Conclusions: These results suggest that circulating IL-6, as well as IL-6 in the bile, may be involved in the pathogenesis of obstructive jaundice, and play an important role in preventing the resolution of obstructive jaundice after PTCD.

The existence of autonomous system of the biliary ducts local immunity was established. The contents of the antibodies and C3-component complement in intraductal bile in patients with purulent cholangitis (PC) is normalizing during an early postoperative period. In a common biliary duct bile while PC a polymorphonuclear neutrophils are regularly revealed, which restore nitroblue tetrazolium (NBT) diffusely. The NBT test application in PC diagnosis is substantiated.

The largest lymphoid organ in the body is the gut and the gut-associated lymphoid tissue. The mucosal immune system faces many challenges in protecting the body from microbial invasion. Its chief function is to maintain a diverse population of mature lymphocytes capable of responding to foreign antigens. This task is accomplished with a variety of unique features that distinguish the mucosal from the systemic immune system. In addition, the mucosal immune system plays a role in inflammatory bowel disease, Whipple disease, autoimmune gastritis, Helicobacter pylori infection, immunoproliferative small intestinal disease, hepatitis A, B, C, D, E, F, and G, autoimmune hepatitis, primary biliary cirrhosis, progressive sclerosing cholangitis, and vanishing bile duct syndrome.

Those people living in industrial regions have increased incidence of chronic disorders of the hepatobiliary system. In postpartum female patients presenting with the above extragenital pathology, there occur with a greater than usual frequency such abnormalities as uterus hypotony, its subinvolution, hypogalactia, with the postpartum septic complications running a graver course. Immune inadequacies and microcirculatory disorders detected in women presenting with chronic disorders of the hepatobiliary system result in the pathological course of the postpartum period.

In 105 patients with chronic inflammatory illness of gallbladder and biliary ducts the generally-accepted therapy have influenced the IgM and IgG contents in serum, the lymphocytes sensibilization to the tissue antigens of gallbladder, liver, pancreas, the titre of antibodies to this antigens only. The authors insist on necessity of supplementary application of immunomodulating agents in the complex of patients treatment, especially if reactive hepatitis or pancreatitis is present.

Neonatal hepatobiliary disorders are now better understood due primarily to new discoveries in molecular genetics, virology, and immunology. Because they are almost always pathologic and require early intervention, the neonatologist must recognize infants with these hepatocellular and ductal cholestatic problems occurring in the first few weeks of life. This article focuses mainly on new developments regarding neonatal metabolic disorders and their potential for gene therapy; perinatal infections, especially those caused by hepatitis B virus, hepatitis C virus, and human immunodeficiency virus; and recent concepts of neonatal hepatitis and biliary atresia, including a review of predictors that influence outcome for infants undergoing Kasai portoenterostomy and liver transplantation.

Overall fifty patients with chronic hepatitis and 50 patients with concurrent pathologies were examined. The patients with chronic active hepatitis and in coexisting pathologies showed more profound depression of the immunity system as well as striking alterations on the iris of the eye. The former patient group received basic therapy, while the latter one were given immunomodulating agents against the background of basic therapy. Iridodiagnosis will, we believe, help in detecting concurrent pathologies of the hepatobiliary and urinary systems. The dynamics of the pathological signs in the iris is strongly related to the clinicoimmunological picture of the illness. Iridodiagnosis is a reliable test of a therapeutic effect in patients with chronic diseases of the hepatobiliary system and in those cases having this medical problem concurrently with the urinary system pathologies.

Rats immunosuppressed by hydrocortisone acetate and a low protein diet were challenged with Cryptosporidium Parvum oocysts and studied on days 10, 35 and 70 post-infection. The biliary tract was found to be a major site of parasite infection. C. parvum was visible in the biliary papillary area in association with a proliferation of highly convoluted tubular glands. The papillary lumen was narrowed, and an upstream dilation with bacterial proliferation was seen. The liver was initially free of lesions, and subsequently exhibited late lesions of cholestasis. Parasites were not found in the pancreatic duct, although pancreatitis was frequently observed. Oocysts were consistently present in the distal portion of the ileum. Both challenged and unchallenged immunosuppressed rats, exhibited widespread focal hepatic infarcts and pyelonephritis. Other organs appeared free of lesions. In addition to the intestine, data identified the biliary tract as a major site of C. parvum infection and as a potential protected reservoir which may sustain a chronic infection.

Ofloxacin was used in the treatment of 124 patients with bronchopulmonary diseases, the diseases of the biliary system and other infectious inflammatory diseases of the internal organs. The microbiological and pharmacokinetic indices as well as the immune status were investigated. The drug proved to be efficient in the treatment of 78.9 per cent of the cases. The pharmacokinetic indices were evident of the fact that the treatment of severe cases should be started with the drug intravenous administration. Ofloxacin had no negative effects on the immune status.

Specific markers for pancreatic or biliary cancer have been developed in the past few years. Ca 19-9 has a good sensitivity but it is also increased in benign cholestasis. Mutations in the p53 gene are commonly reported in pancreatic cancer and can be detected by a serological analysis. The aim of this work was to find out the sensitivity and specificity of this new assay in diagnosing cancer of the pancreas or of the bile ducts. The presence of antibodies against p53 was determined by an enzyme linked immunosorbent assay (ELISA) in 29 patients with pancreatic cancer, 33 with biliary tract cancer, and 33 with benign biliary or pancreatic diseases as controls. p53 Antibodies were detected in eight of 29 patients with pancreatic cancer (28%), in five of 33 patients with biliary tract (15%), and in one patient (3%) with stones of the common bile duct. The sensitivity and the specificity for the diagnosis of malignant biliary or pancreatic diseases were 21% and 96% respectively. It is concluded that the presence of p53 antibodies in the serum of patients with pancreatic and biliary diseases is specific for malignancy and independent from the presence of cholestatic disease.

Antineutrophil cytoplasm autoantibodies are useful diagnostic serologic markers for a variety of well-known primary vasculitic syndromes, including Wegener's granulomatosis, microscopic polyangiitis, and idiopathic necrotizing and crescentic glomerulo-nephritis. More recently antineutrophil cytoplasm autoantibodies have been found in other vasculitic syndromes, such as Churg-Strauss syndrome, Henoch-Schönlein purpura, and some nonvasculitic diseases such as rheumatoid arthritis, inflammatory bowel disease, and autoimmune hepatobiliary diseases. There is now evidence to suggest that infection might be an important etiologic factor in the development of antineutrophil cytoplasm autoantibody-associated vasculitides. This link has been strengthened by in vitro data that suggest that antineutrophil cytoplasm autoantibodies are directly involved in the pathogenesis of antineutrophil cytoplasm autoantibody-associated vasculitides.

The expression of Lewis Y antigen (a blood group-related antigen containing type 2 chain) in hepatocytes was examined immunohistochemically, using the monoclonal antibody F-3, in a total of 530 liver specimens consisting of normal livers and various hepatobiliary diseased livers. Lewis Y was rarely expressed in the hepatocytes in histologically normal livers (20 cases) or in livers from patients with nonspecific reactive change or chronic persistent hepatitis, in viral livers (19 cases), autoimmune etiology livers (3 cases), or acute hepatitis-like change of autoimmune etiology livers (7 cases). In chronic active hepatitis of viral (132 cases) and autoimmune etiology livers (20 cases) with or without cirrhosis, the incidence of membranous expression of Lewis Y in clustered hepatocytes of viral and autoimmune etiology livers was 21 and 0% of mild chronic active hepatitis; 69 and 25% of moderate degree; 85 and 50% of severe degree; and 87 and 100% of cirrhosis, respectively. In alcoholic liver disease (27 cases), the incidence of membranous expression of Lewis Y in clustered hepatocytes was 18, 75, and 100% in mild fibrosis, moderate fibrosis, and cirrhosis, respectively. Such membranous expression of Lewis Y was not found in the early or late stages of the biliary diseases examined, primary biliary cirrhosis (226 cases), primary sclerosing cholangitis (8 cases), or extrahepatic biliary obstruction (22 cases).(ABSTRACT TRUNCATED AT 250 WORDS)

Background/aims: A strong association exists between ulcerative colitis and primary sclerosing cholangitis (PSC). Previously, the presence of a unique epitope shared by colon and biliary epithelial cells was shown by using the novel monoclonal antibody (MAb) 7E12H12 developed against a colonic epithelial protein. In the present study, the presence of circulating autoantibody in PSC against this peptide was examined., Methods: Sera from 16 patients with PSC, 13 with primary biliary cirrhosis, 6 with secondary biliary stricture, and 6 with chronic liver diseases and 10 normal subjects were used. An inhibition immunoperoxidase assay using the 7E12H12 MAb was developed against sections of bile duct and gallbladder. Sera were also examined in an enzyme-linked immunosorbent assay (ELISA) against the gallbladder extract enriched in 7E12H12-reactive protein., Results: About two thirds of the sera from patients with PSC blocked the binding of 7E12H12 MAb on the bile duct and gallbladder, whereas non-PSC sera did not. In the ELISA, 93% of PSC sera had circulating immunoglobulin G antibodies against the enriched gallbladder extract. The reactivity of sera from the PSC group was significantly (P < 0.01 to P < 0.0001) higher than in each of the non-PSC groups., Conclusions: Sera from patients with PSC contains autoantibodies against a cross-reactive peptide shared by colon and biliary epithelial cells.

We examined the expression of Lewis antigens, particularly Lewis Y, on the intrahepatic biliary epithelial cells in normal livers and various hepatobiliary diseases with immunohistochemical and immunoelectron microscopic methods. In normal livers, Lewis Y was consistently and generally negative in the bile ductules and small bile ducts, respectively. This antigen was frequently and strongly expressed on these ducts and ductules showing variable pathological changes such as necroinflammation and proliferation in a majority of hepatobiliary diseases independent on their etiology, whereas a majority of normal-appearing bile ducts and ductules in these pathological conditions were negative. Immunoelectron microscopically, gold particles suggesting the presence of Lewis Y were demonstrated on microvilli facing the biliary lumen, lateral cell membranes, secretory granules and Golgi apparatus of abnormal biliary epithelial cells in various hepatobiliary diseases. These data suggest that neoexpression of Lewis Y antigen is a highly sensitive, nonspecific phenotypic change of carbohydrate residues occurring in the abnormal biliary epithelial cells in various hepatobiliary diseases.

Carcinoembryonic antigen (CEA) has been reported in benign and malignant epithelium of the gall bladder, although cross-reactivity with CEA-related antigens cannot be excluded. We have investigated the immunoreactivity of three monoclonal and two polyclonal antisera to CEA in benign and malignant epithelium of the gall bladder, extrahepatic bile ducts, and ampulla of Vater. The results varied with the antisera, due to cross-reactivity with CEA-related antigens and according to the epitope specificities. Little CEA was found in benign epithelium using monoclonal antisera or following absorption of a polyclonal antiserum from Dako with human liver powder. The latter was the most reliable at detecting malignant epithelium of the gall bladder and extrahepatic bile ducts. All antisera showed equal immunoreactivity in tumours of the ampulla of Vater. The differences seen in the immunoreactivities between tumours of the upper and lower extrahepatic biliary tract probably indicate a variation in the occurrence of CEA epitopes.

Sera from 35 out of 655 patients with suspected or confirmed hepatobiliary diseases were positive for anti-neutrophil antibodies with a perinuclear staining pattern (p-ANCA). Nineteen of these sera did not react with myeloperoxidase (MPO), Cathepsin G or Elastase, the three proposed antigens of p-ANCAs. No distinct antigen for these sera could be characterized by western blot techniques with fractionated granulocyte proteins.