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Grama A, Mititelu A, Sîrbe C, Benţa G, Pop TL. Immune-mediated cholangiopathies in children: the need to better understand the pathophysiology for finding the future possible treatment targets. Front Immunol 2023; 14:1206025. [PMID: 37928553 PMCID: PMC10623351 DOI: 10.3389/fimmu.2023.1206025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/28/2023] [Indexed: 11/07/2023] Open
Abstract
Cholangiopathies are defined as focal or extensive damage of the bile ducts. According to the pathogenetic mechanism, it may be immune-mediated or due to genetic, infectious, toxic, vascular, and obstructive causes. Their chronic evolution is characterized by inflammation, obstruction of bile flow, cholangiocyte proliferation, and progression toward fibrosis and cirrhosis. Immune-mediated cholangiopathies comprise primary sclerosing cholangitis (PSC), autoimmune cholangitis and IgG4-associated cholangitis in adults and biliary atresia (BA), neonatal sclerosing cholangitis (NSC) in children. The main purpose of this narrative review was to highlight the similarities and differences among immune-mediated cholangiopathies, especially those frequent in children in which cholangiocyte senescence plays a key role (BA, NSC, and PSC). These three entities have many similarities in terms of clinical and histopathological manifestations, and the distinction between them can be hard to achieve. In BA, bile duct destruction occurs due to aggression of the biliary cells due to viral infections or toxins during the intrauterine period or immediately after birth. The consequence is the activation of the immune system leading to severe inflammation and fibrosis of the extrahepatic biliary tract, lumen stenosis, and impairment of the biliary flow. PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to secondary biliary cirrhosis. It is a multifactorial disease that occurs because of genetic predisposition [human leukocyte antigen (HLA) and non-HLA haplotypes], autoimmunity (cellular immune response, autoantibodies, association with inflammatory bowel disease), environmental factors (infections or toxic bile), and host factors (intestinal microbiota). NSC seems to be a distinct subgroup of childhood PSC that appears due to the interaction between genetic predisposition (HLA B8 and DR3) and the disruption of the immune system, validated by elevated IgG levels or specific antibodies [antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA)]. Currently, the exact mechanism of immune cholangiopathy is not fully understood, and further data are required to identify individuals at high risk of developing these conditions. A better understanding of the immune mechanisms and pathophysiology of BA, NSC, and PSC will open new perspectives for future treatments and better methods of preventing severe evolution.
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Affiliation(s)
- Alina Grama
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Alexandra Mititelu
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Claudia Sîrbe
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Gabriel Benţa
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Tudor Lucian Pop
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
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D’Incà R, Sturniolo G. Biomarkers in IBD: What to Utilize for the Diagnosis? Diagnostics (Basel) 2023; 13:2931. [PMID: 37761298 PMCID: PMC10527829 DOI: 10.3390/diagnostics13182931] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/05/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
The role of biomarkers in the diagnosis of inflammatory bowel disease is not fully characterized. C-reactive protein has a short half-life and elevates quickly after the onset of an inflammatory process; the performance is better in Crohn's disease than in ulcerative colitis. Erythrocyte sedimentation rate is easy to determine, widely available, and cheap, but the long half-life, the influence of age, anemia, smoking, and drugs limit its usefulness. Fecal markers have good specificity, but suboptimal accuracy. Microbial antibodies and novel immunological markers show promise but need further evidence before entering clinical practice. Proteomic methods could represent the dawn of a new era of stool protein/peptide biomarker panels able to select patients at risk of inflammatory bowel disease.
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Affiliation(s)
- Renata D’Incà
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35124 Padua, Italy
| | - Giulia Sturniolo
- Department of Women’s and Children’s Health, University of Padua, 35128 Padova, Italy
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PR3-ANCAs Detected by Third-Generation ELISA Predicts Severe Disease and Poor Survival in Primary Sclerosing Cholangitis. Diagnostics (Basel) 2022; 12:diagnostics12112682. [PMID: 36359524 PMCID: PMC9689935 DOI: 10.3390/diagnostics12112682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/21/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
A highly sensitive detection of anti-neutrophil cytoplasmic antibodies to serine proteinase-3 (PR3-ANCAs) aids in the serological diagnosis of autoimmune liver disorders and the prediction of severity in primary sclerosing cholangitis (PSC). Here, we evaluate a novel third-generation ELISA for the detection of PR3-ANCAs. In total, 309 patients with PSC, 51 with primary biliary cholangitis (PBC), and 120 healthy blood donors (BD) were analyzed. For the survival analysis in PSC, the outcome was defined as liver-transplantation-free survival during the follow-up. Positive PR3-ANCA levels were found in 74/309 (24.0%) of patients with PSC. No BDs and one patient with PBC demonstrated PR3-ANCA positivity. PR3-ANCAs were revealed as independent predictors for a poor PSC outcome (study endpoint: liver transplantation/death, log-rank test, p = 0.02). PR3-ANCA positivity, lower albumin levels, and higher bilirubin concentrations were independent risks of a poor survival (Cox proportional-hazards regression analysis, p < 0.05). The Mayo risk score for PSC was associated with PR3-ANCA positivity (p = 0.01) and the disease severity assessed with a model of end-stage liver disease (MELD) and extended MELD-Na (p < 0.05). PR3-ANCAs detected by a third-generation ELISA are diagnostic and prognostic markers for PSC. Their wider use could help to identify patients who are at-risk of a more severe disease.
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Abstract
Chronic liver disease in pregnancy is rare. Historically, many chronic liver diseases were considered contraindications to pregnancy; however, with current monitoring and treatment strategies, pregnancy may be considered in many cases. Preconception and initial antepartum consultation should focus on disease activity, medication safety, risks of pregnancy, as well as the need for additional monitoring during pregnancy. In most cases, a multidisciplinary approach is necessary to ensure optimal maternal and fetal outcomes. Despite improving outcomes, pregnancy in women with the chronic liver disease remains high risk.
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Lopens S, Krawczyk M, Papp M, Milkiewicz P, Schierack P, Liu Y, Wunsch E, Conrad K, Roggenbuck D. The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia. AUTO- IMMUNITY HIGHLIGHTS 2020; 11:6. [PMID: 32178720 PMCID: PMC7077156 DOI: 10.1186/s13317-020-00129-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/06/2020] [Indexed: 12/22/2022]
Abstract
Unlike in other autoimmune liver diseases such as autoimmune hepatitis and primary biliary cholangitis, the role and nature of autoantigenic targets in primary sclerosing cholangitis (PSC), a progressive, chronic, immune-mediated, life threatening, genetically predisposed, cholestatic liver illness, is poorly elucidated. Although anti-neutrophil cytoplasmic antibodies (ANCA) have been associated with the occurrence of PSC, their corresponding targets have not yet been identified entirely. Genome-wide association studies revealed a significant number of immune-related and even disease-modifying susceptibility loci for PSC. However, these loci did not allow discerning a clear autoimmune pattern nor do the therapy options and the male gender preponderance in PSC support a pathogenic role of autoimmune responses. Nevertheless, PSC is characterized by the co-occurrence of inflammatory bowel diseases (IBD) demonstrating autoimmune responses. The identification of novel autoantigenic targets in IBD such as the major zymogen granule membrane glycoprotein 2 (GP2) or the appearance of proteinase 3 (PR3) autoantibodies (autoAbs) have refocused the interest on a putative association of loss of tolerance with the IBD phenotype and consequently with the PSC phenotype. Not surprisingly, the report of an association between GP2 IgA autoAbs and disease severity in patients with PSC gave a new impetus to autoAb research for autoimmune liver diseases. It might usher in a new era of serological research in this field. The mucosal loss of tolerance against the microbiota-sensing GP2 modulating innate and adaptive intestinal immunity and its putative role in the pathogenesis of PSC will be elaborated in this review. Furthermore, other potential PSC-related autoantigenic targets such as the neutrophil PR3 will be discussed. GP2 IgA may represent a group of new pathogenic antibodies, which share characteristics of both type 2 and 3 of antibody-mediated hypersensitive reactions according to Coombs and Gell.
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Affiliation(s)
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Hospital, Saarland University, Homburg/Saar, Germany
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Yudong Liu
- Department of Laboratory Medicine, Peking University People's Hospital, Beijing, China
| | - Ewa Wunsch
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Karsten Conrad
- Institute of Immunology, Technical University Dresden, Dresden, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany.
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, Universitätsplatz 1, 01968, Senftenberg, Germany.
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Gossard AA, Gores GJ. Primary Sclerosing Cholangitis: What the Gastroenterologist and Hepatologist Needs to Know. Clin Liver Dis 2017; 21:725-737. [PMID: 28987259 DOI: 10.1016/j.cld.2017.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic biliary tract disease characterized by segmental strictures. The disease is progressive with no proven treatments and may eventually lead to cirrhosis and end-stage liver disease. Abrupt changes in liver biochemistries, pain, and/or cholangitis may suggest a dominant stricture amenable to endoscopic therapy or the development of cholangiocarcinoma. Patients with PSC are at increased risk of cholangiocarcinoma. There is a strong association with inflammatory bowel disease, and an associated increased risk of colorectal cancer. Colonoscopy every 1 to 2 years is appropriate.
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Affiliation(s)
- Andrea A Gossard
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55901, USA.
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55901, USA
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Ganji-Arjenaki M, Nasri H, Rafieian-Kopaei M. Nephrolithiasis as a common urinary system manifestation of inflammatory bowel diseases; a clinical review and meta-analysis. J Nephropathol 2017; 6:264-269. [PMID: 28975110 PMCID: PMC5607992 DOI: 10.15171/jnp.2017.42] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 03/29/2017] [Indexed: 12/18/2022] Open
Abstract
CONTEXT The extra-intestinal manifestations of inflammatory bowel disease (IBD) are common and involve other organs or systems for example; urinary system. EVIDENCE ACQUISITIONS For this review, we used a variety of sources by searching through Web of Science, PubMed, EMBASE, Scopus and directory of open access journals (DOAJ). RESULTS Urinary complications may occur in up to 22% of patients and nephrolithiasis or renal/kidney stones have been suggested to be a common manifestation of disease in forms of uric acid, calcium phosphate or calcium oxalate. We performed a meta-analysis on five clinical trials and reported that correlation between IBD and formation of stone in renal system is positive and significant (Fix-effect model; CI: 95%, P <0.001, and randomeffect model; CI: 95%, P = 0.03). CONCLUSIONS Based on the reports of the clinical trials, calcium oxalate is more prevalent in Crohn's disease (CD) than in ulcerative colitis (UC).
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Affiliation(s)
| | - Hamid Nasri
- Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Mitra S, Minz RW. Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist. Int J Surg Pathol 2016; 24:576-85. [PMID: 27388199 DOI: 10.1177/1066896916657643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.
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Affiliation(s)
- Suvradeep Mitra
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ranjana Walker Minz
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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9
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Kevans D, Waterman M, Milgrom R, Xu W, Van Assche G, Silverberg M. Serological markers associated with disease behavior and response to anti-tumor necrosis factor therapy in ulcerative colitis. J Gastroenterol Hepatol 2015; 30:64-70. [PMID: 25041458 DOI: 10.1111/jgh.12661] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Information is limited on the relationship between serological markers and disease behavior and anti-tumor necrosis factor-α (anti-TNF) therapy response in ulcerative colitis (UC). This study aimed to determine the association between serological markers and unfavorable UC behavior defined as need for colectomy or UC-related hospitalization. The association between serological markers and requirement for and outcome of anti-TNF therapy was also evaluated. METHODS Two hundred thirty patients were studied. Requirement for colectomy, UC-related hospitalization, and anti-TNF therapy were documented. Response to anti-TNF therapy at 1 year and rates of therapy discontinuation were recorded. Titers of perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs), anti-Saccharomyces cerevisiae antibody (ASCA), and antibody to Escherichia Coli outer membrane porin (anti-OmpC) were determined. Antibody reference ranges were used to dichotomize subjects into seropositive and seronegative groups. Where multiple tests were performed, P-values were Bonferroni corrected (pcorr). RESULTS Extensive colitis was associated with requirement for colectomy and UC-related hospitalization, HR 7.7 (95% confidence interval [CI] 1.9-32.2) pcorr = 0.03 and HR 2.7 (95% CI 1.5-4.6), pcorr = 0.006, respectively. No serological variable was associated with unfavorable UC behavior. Anti-OmpC positivity was associated with a lack of response to anti-TNF therapy at 1 year (odds ratio 0.14 [95% CI 0.03-0.60], pcorr = 0.04) and increased likelihood of therapy discontinuation (HR 2.2 [95% CI 1.1-4.7], P = 0.03). CONCLUSION Extensive colitis is associated with unfavorable disease course in UC. Anti-OmpC holds promise as a biomarker of anti-TNF therapy response in UC; however, prospective studies are required before it can be incorporated into routine clinical practice.
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Affiliation(s)
- David Kevans
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
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Marchioni Beery RM, Vaziri H, Forouhar F. Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis: a Review Featuring a Women's Health Perspective. J Clin Transl Hepatol 2014; 2:266-84. [PMID: 26357630 PMCID: PMC4521232 DOI: 10.14218/jcth.2014.00024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 10/15/2014] [Accepted: 10/19/2014] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are two major types of chronic cholestatic liver disease. Each disorder has distinguishing features and variable progression, but both may ultimately result in cirrhosis and hepatic failure. The following offers a review of PBC and PSC, beginning with a general overview of disease etiology, pathogenesis, diagnosis, clinical features, natural course, and treatment. In addition to commonly associated manifestations of fatigue, pruritus, and fat-soluble vitamin deficiency, select disease-related topics pertaining to women's health are discussed including metabolic bone disease, hyperlipidemia and cardiovascular risk, and pregnancy-related issues influencing maternal disease course and birth outcomes. This comprehensive review of PBC and PSC highlights some unique clinical considerations in the care of female patients with cholestatic liver disease.
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Affiliation(s)
- Renée M. Marchioni Beery
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Renée M. Marchioni Beery, DO, Division of Internal Medicine, Department of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-1845, USA. Tel: +01-860-679-3158, Fax: +01-860-679-3159. E-mail:
| | - Haleh Vaziri
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - Faripour Forouhar
- Department of Pathology and Lab Medicine, University of Connecticut Health Center, Farmington, CT, USA
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Stinton LM, Bentow C, Mahler M, Norman GL, Eksteen B, Mason AL, Kaplan GG, Lindkvist B, Hirschfield GM, Milkiewicz P, Cheung A, Janssen HLA, Fritzler MJ. PR3-ANCA: a promising biomarker in primary sclerosing cholangitis (PSC). PLoS One 2014; 9:e112877. [PMID: 25397578 PMCID: PMC4232573 DOI: 10.1371/journal.pone.0112877] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 10/18/2014] [Indexed: 12/12/2022] Open
Abstract
Background and Aims The only recognized biomarker for primary sclerosing cholangitis (PSC) is atypical anti-neutrophil cytoplasmic antibodies (aANCA), which, in addition to having low sensitivity and specificity, is an indirect immunofluorescence (IIF) test lacking the advantages of high throughput and objectivity. Recent reports have shown that antibodies to proteinase-3 (PR3-ANCA) might add diagnostic value in inflammatory bowel disease (IBD), specifically in ulcerative colitis (UC). As PSC is associated with IBD, the objective of this study was to evaluate the frequency and clinical significance of PR3-ANCA in a large cohort of patients. Methods A total of 244 PSC and 254 control [autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), hepatitis C viral infection (HCV), hepatitis B viral infection (HBV), and healthy controls] sera and their clinical correlations were retrospectively analyzed for PR3-ANCA determined by ELISA and a new chemiluminescence immunoassay (CIA). Testing was also performed for aANCA by IIF. Results When measured by CIA, PR3-ANCA was detected in 38.5% (94/244) of PSC patients compared to 10.6% (27/254) controls (p<0.0001). By ELISA, PR3-ANCA was detected in 23.4% (57/244) of PSC patients compared to 2.7% (6/254) controls (p<0.0001). PR3-ANCA in PSC patients was not associated with the presence or type of underlying IBD, and, in fact, it was more frequent in Crohn's disease (CD) patients with PSC than previously reported in CD alone. PR3-ANCA in PSC measured by CIA correlated with higher liver enzymes. Conclusion PR3-ANCA is detected in a significant proportion of PSC patients compared to other liver diseases including PBC and AIH. PR3-ANCA is associated with higher liver enzyme levels in PSC, and is not solely related to underlying IBD.
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Affiliation(s)
- Laura M. Stinton
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- * E-mail:
| | - Chelsea Bentow
- Inova Diagnostics, Inc., San Diego, California, United States of America
| | - Michael Mahler
- Inova Diagnostics, Inc., San Diego, California, United States of America
| | - Gary L. Norman
- Inova Diagnostics, Inc., San Diego, California, United States of America
| | - Bertus Eksteen
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Andrew L. Mason
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Gilaad G. Kaplan
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Bjorn Lindkvist
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gideon M. Hirschfield
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom
| | - Piotr Milkiewicz
- Department of General, Transplant and Liver Surgery, Warsaw Medical University, Warsaw, Poland
- Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland
| | - Angela Cheung
- University Health Network, Division of Gastroenterology, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Harry L. A. Janssen
- University Health Network, Division of Gastroenterology, Toronto Western Hospital, Toronto, Ontario, Canada
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Fickert P, Pollheimer MJ, Beuers U, Lackner C, Hirschfield G, Housset C, Keitel V, Schramm C, Marschall HU, Karlsen TH, Melum E, Kaser A, Eksteen B, Strazzabosco M, Manns M, Trauner M. Characterization of animal models for primary sclerosing cholangitis (PSC). J Hepatol 2014; 60:1290-303. [PMID: 24560657 PMCID: PMC4517670 DOI: 10.1016/j.jhep.2014.02.006] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 02/01/2014] [Accepted: 02/08/2014] [Indexed: 01/17/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.
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Affiliation(s)
- Peter Fickert
- Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University of Graz, Austria.
| | - Marion J. Pollheimer
- Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria,Institute of Pathology, Medical University of Graz, Austria
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, The Netherlands
| | | | - Gideon Hirschfield
- Centre for Liver Research, Institute of Biomedical Research, School of Immunity and Infection, University of Birmingham, UK
| | - Chantal Housset
- UPMC Univ Paris 06 & INSERM, UMR-S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France
| | - Verena Keitel
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Düsseldorf Germany
| | | | - Hanns-Ulrich Marschall
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, The Sahlgrenska Academy, Sweden
| | - Tom H. Karlsen
- Division of Gastroenterology and Hepatology, Department of Medicine, Rikshospitalet, Oslo, Norway,Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Espen Melum
- Division of Gastroenterology and Hepatology, Department of Medicine, Rikshospitalet, Oslo, Norway,Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooek's Hospital, UK
| | - Bertus Eksteen
- Centre for Liver Research, MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, and The Queen Elizabeth Hospital, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Mario Strazzabosco
- Section of Gastroenterology, University of Milan-Bicocca, Milan, Italy,Liver Center, Yale University School of Medicine, United States
| | - Michael Manns
- Division of Gastroenterology, Hepatology and Endocrinology, Medical University Hannover, Germany
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
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Saadi M, Yu C, Othman MO. A Review of the Challenges Associated with the Diagnosis and Therapy of Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2014; 2:45-52. [PMID: 26357617 PMCID: PMC4548359 DOI: 10.14218/jcth.2013.00021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/01/2014] [Accepted: 02/04/2014] [Indexed: 12/12/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disease that often leads to the development of cirrhosis. Complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, dominant biliary strictures, gallstones, and hepatobiliary malignancies, most commonly cholangiocarcinoma (CCA). Despite the presumed autoimmune etiology of PSC, a clear benefit from immunosuppressive agents has not yet been established, and their use is limited by their side effects. Endoscopy is required in evaluation of biliary strictures in PSC to rule out the possibility of CCA. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease. However, disease recurrence can be a source of morbidity and mortality as transplanted patients survive longer. Further studies are needed to develop an optimal therapeutic strategy for patients with PSC to decrease the incidence of complications of the disease, to decrease the need for transplantation, and to extend life expectancy.
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Affiliation(s)
- Mohammed Saadi
- Department of Medicine, Division of Gastroenterology and Hepatology, Texas Tech University Health Science Center-Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Christine Yu
- Department of Medicine, Division of Gastroenterology and Hepatology, Texas Tech University Health Science Center-Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Mohamed O Othman
- Department of Medicine, Division of Gastroenterology and Hepatology, Texas Tech University Health Science Center-Paul L. Foster School of Medicine, El Paso, TX, USA
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Lenzen H, Weismüller TJ, Negm AA, Wlecke J, Loges S, Strassburg CP, Manns MP, Lankisch TO. Antineutrophil cytoplasmic antibodies in bile are associated with disease activity in primary sclerosing cholangitis. Scand J Gastroenterol 2013; 48:1205-12. [PMID: 23957616 DOI: 10.3109/00365521.2013.825313] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology. The role of antineutrophil cytoplasmic antibodies (ANCAs) in the serum of patients with PSC remains unclear. We hypothesized that ANCA may be detectable in bile, potentially providing diagnostic and prognostic information. METHODS. Serum and bile were prospectively collected during endoscopic retrograde cholangiography (ERC) in 72 patients with PSC and other non-PSC obstructive biliary diseases. ANCA measurements were performed by indirect immunofluorescence (IIF). RESULTS. Immunoglobulin G (IgG) ANCA was detected significantly more often in the bile of PSC patients (15/39; 38%) than without (2/33; 6%) (p = 0.001). IgG ANCA in bile was associated with a ten times higher risk of PSC (p = 0.005). In addition, IgG ANCA positivity in bile was associated with the presence of dominant strictures (p = 0.03), cholangiographic severity (p = 0.004), number of ERC (p = 0.01) and interventions performed (p = 0.03). However, IgG ANCA in bile did not correlate with transplantation, cholangiocarcinoma or death. No association was observed between ANCA positivity in sera and ANA and ASCA positivity in sera or bile with the above-mentioned clinical features. CONCLUSIONS. The presence of ANCA in the bile of patients with PSC is a novel finding and highly suggestive of PSC. Biliary IgG ANCA correlates with the severity of bile duct strictures and the ensuing number of ERCs and interventions. Therefore, a positive ANCA status in bile may serve as a diagnostic and prognostic marker of the disease progression and biliary complications.
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Affiliation(s)
- Henrike Lenzen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
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15
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Deniziaut G, Ballot E, Johanet C. Antineutrophil cytoplasmic auto-antibodies (ANCA) in autoimmune hepatitis and primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2013; 37:105-7. [PMID: 22998811 DOI: 10.1016/j.clinre.2012.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 07/06/2012] [Accepted: 07/10/2012] [Indexed: 02/04/2023]
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Abstract
The search for the underlying trigger of an inappropriate inflammatory reaction characteristic of inflammatory bowel diseases (IBD) has led to the discovery of several antibodies. The panel of serologic markers for IBD is rapidly expanding. Serologic markers hold the promise of helping researchers and clinicians to better understand IBD heterogeneity and natural history. The real importance of the antibodies produced against various microbial and autoantigens is still uncertain. Whether these antibodies play a primary role in the pathogenesis of IBD, or their presence is only a consequence of the inflamed mucosa is a fundamental question that remains to be clarified. The impact of the routine evaluation of these serologic markers in the everyday clinical IBD diagnostic algorithm is questionable due to their limited sensitivity. Despite their great potential, the routine use of serologic markers for diagnosis and follow-up is currently not justified. However, their correlation with disease phenotype and behavior is more established. A combination of serum markers has been shown to be of more value compared to using single markers alone. The ongoing challenge is how to best utilize these serologic markers to provide clinically relevant information in a cost-effective manner. Further prospective clinical trials are needed to determine their exact role in pathogenesis and practical clinical importance. We review the current standpoint of the clinical impact of various established and newly suggested markers in Crohn's disease and ulcerative colitis.
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Affiliation(s)
- László Herszényi
- Second Department of Medicine, Semmelweis University, Budapest, Hungary.
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17
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Abstract
Cholestasis develops either from a defect in bile synthesis, impairment in bile secretion, or obstruction to bile flow, and is characterized by an elevated serum alkaline phosphatase and gamma-glutamyltransferase disproportionate to elevation of aminotransferase enzymes. Key elements to the diagnostic workup include visualization of the biliary tree by cholangiography and evaluation of liver histology. The hope is that recent advances in understanding the genetic factors and immune mechanisms involved in the pathogenesis of cholestasis will lead to newer therapeutic interventions in the treatment of these diseases.
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Affiliation(s)
- Asma Siddique
- Department of Gastroenterology, Center for Liver Disease, Digestive Disease Institute, Seattle, WA 98111, USA
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18
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Pollheimer MJ, Halilbasic E, Fickert P, Trauner M. Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2011; 25:727-39. [PMID: 22117638 PMCID: PMC3236286 DOI: 10.1016/j.bpg.2011.10.009] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 10/25/2011] [Indexed: 01/31/2023]
Abstract
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
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Affiliation(s)
- Marion J. Pollheimer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria,Corresponding author. Tel.:+43 (0) 1 40400 4741; fax: +43 (0) 1 40400 4735.
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19
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Arai R. Serologic markers: impact on early diagnosis and disease stratification in inflammatory bowel disease. Postgrad Med 2010; 122:177-85. [PMID: 20675980 DOI: 10.3810/pgm.2010.07.2184] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is difficult to diagnose, and differentiating between ulcerative colitis (UC) and Crohn's disease (CD) can be challenging. Overlapping symptoms of UC and CD often delay diagnosis, despite availability of endoscopic, radiologic, and histologic tools. This delay in diagnosis is quite common in clinical practice, which may also delay initiation of appropriate treatment. Abnormal immune responses found in IBD have led to the use of serum biomarkers (eg, anti-Saccharomyces cerevisiae antibody [ASCA], perinuclear antineutrophil cytoplasmic antibody [pANCA], antibodies to flagellin [anti-CBir1]) to improve diagnostic confidence in IBD. These biomarkers are beginning to be used to stratify patients with UC and CD according to disease phenotype and risk of complications. Associations between quantity and quality of immune reactivity and severe disease phenotypes are increasingly evident. This suggests that serologic panels of multiple IBD biomarkers can be used to identify the relative risk of progression to complicated disease behaviors, and that this information may ultimately impact therapeutic decisions. This review discusses the diagnostic process and challenges in IBD, with emphasis on the role that serologic markers may play in addressing these challenges.
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Affiliation(s)
- Ronen Arai
- Digestive Care of North Broward, Coral Springs, FL 33065, USA.
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20
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Zisman TL, Rubin DT. Novel diagnostic and prognostic modalities in inflammatory bowel disease. Med Clin North Am 2010; 94:155-78. [PMID: 19944803 DOI: 10.1016/j.mcna.2009.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease remains a complex disease with variable clinical presentations and often nonspecific symptoms. Physicians must rely on diagnostic tools for clarification of disease diagnosis and for guiding management of patients with established disease. Advances in radiologic imaging modalities facilitate early and accurate detection of luminal disease and extraluminal complications. The introduction and dissemination of small bowel capsule endoscopy and double-balloon enteroscopy permit detailed visualization and sampling of the mucosa throughout the entire bowel. Serologic biomarkers are evolving as a valuable tool to clarify diagnosis and stratify patients by disease phenotypes and patterns of behavior. Neutrophil-derived fecal biomarkers are emerging as useful surrogate markers of intestinal inflammation with the potential for a variety of clinical applications, but their application to clinical management has not yet been clarified.
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Affiliation(s)
- Timothy L Zisman
- Division of Gastroenterology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356424, Seattle, WA 98195, USA
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21
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Zisman TL, Rubin DT. Novel diagnostic and prognostic modalities in inflammatory bowel disease. Gastroenterol Clin North Am 2009; 38:729-52. [PMID: 19913211 DOI: 10.1016/j.gtc.2009.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Inflammatory bowel disease remains a complex disease with variable clinical presentations and often nonspecific symptoms. Physicians must rely on diagnostic tools for clarification of disease diagnosis and for guiding management of patients with established disease. Advances in radiologic imaging modalities facilitate early and accurate detection of luminal disease and extraluminal complications. The introduction and dissemination of small bowel capsule endoscopy and double-balloon enteroscopy permit detailed visualization and sampling of the mucosa throughout the entire bowel. Serologic biomarkers are evolving as a valuable tool to clarify diagnosis and stratify patients by disease phenotypes and patterns of behavior. Neutrophil-derived fecal biomarkers are emerging as useful surrogate markers of intestinal inflammation with the potential for a variety of clinical applications, but their application to clinical management has not yet been clarified.
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Affiliation(s)
- Timothy L Zisman
- Division of Gastroenterology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356424, Seattle, WA 98195, USA
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22
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McPartland KJ, Lewis WD, Gordon FD, Pomfret EA, Pomposelli JJ, Jenkins R, Khettry U. Post-liver transplant cholestatic disorder with biliary strictures: De novo versus recurrent primary sclerosing cholangitis. Pathol Int 2009; 59:312-6. [DOI: 10.1111/j.1440-1827.2009.02371.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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23
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Papp M, Altorjay I, Lakos G, Tumpek J, Sipka S, Dinya T, Palatka K, Veres G, Udvardy M, Lakatos PL. Evaluation of the combined application of ethanol-fixed and formaldehyde-fixed neutrophil substrates for identifying atypical perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2009; 16:464-470. [PMID: 19193830 PMCID: PMC2668288 DOI: 10.1128/cvi.00002-09] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2009] [Revised: 01/21/2009] [Accepted: 01/26/2009] [Indexed: 01/14/2023]
Abstract
No clear guidelines for indirect immunofluorescence (IIF) detection and interpretation of antineutrophil cytoplasmic antibodies (ANCA) have been proposed for inflammatory bowel diseases (IBD). We evaluated the reliability of the combined use of ethanol- and formalin-fixed neutrophil substrates to identify atypical perinuclear ANCA (P-ANCA) by IIF under routine laboratory circumstances. A total of 204 IBD patients were assessed with four different fluorescent substrates in two distinct laboratories. Antibodies against myeloperoxidase, proteinase-3, and other specific granule proteins (elastase, lactoferrin, cathepsin G, lysozyme, and bactericidal permeability-increasing protein) were measured by an enzyme-linked immunosorbent assay. The combined application of ethanol- and formalin-fixed slides to detect atypical P-ANCA resulted in a lack of agreement between assays (kappa, < or =0.39) in the interassay study and moderate agreement in the interobserver study (kappa, 0.42). After atypical and typical P-ANCA patterns were combined, the consensus improved greatly. A total of 26.9% of patients were P-ANCA positive by at least two tests (44.3% of ulcerative colitis [UC] and 13.1% of Crohn's disease [CD] patients; P < 0.0001), while overall ANCA positivity was 22.5% to 34.8%. The combined application of ethanol-fixed and formaldehyde-fixed neutrophil substrates did not facilitate differentiation between P-ANCA and atypical P-ANCA, and the results were not consistent when substrates from different sources were used. Combining all P-ANCA ensures the highest sensitivity and specificity in differentiating UC from CD.
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Affiliation(s)
- Maria Papp
- 2nd Department of Medicine, University of Debrecen, Hungary.
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24
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Shorbagi A, Bayraktar Y. Primary sclerosing cholangitis--what is the difference between east and west? World J Gastroenterol 2008. [PMID: 18609680 DOI: 10.3748/wig.3974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, progressive, cholestatic liver disease characterized by inflammation and fibrotic obliteration of the hepatic biliary tree. It is commonly associated with inflammatory bowel disease (IBD). A number of complications can occur which require special consideration, the most important of which is the development of cholangiocellular carcinoma (CCC). Unfortunately, no medical therapy is currently available for the underlying liver disease. Liver transplantation is an effective, life-extending option for patients with advanced PSC. Geographical variations between East and West include a second peak for age with a lower association with IBD in a Japanese population and female predominance in a lone study from Turkey. The clinical and biochemical Mayo criteria may not be universally applicable, as different patients show variations regarding the initial presentation and natural course of the disease. Directing research towards explaining these geographical differences and understanding the pathogenesis of PSC is required in order to develop better therapies for this devastating disease.
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Affiliation(s)
- Ali Shorbagi
- Hacettepe University, School of Medicine, Department of Internal Medicine, Gastroenterology clinic, Sihhiye 06100, Ankara, Turkey.
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25
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Schoepfer AM, Schaffer T, Seibold-Schmid B, Müller S, Seibold F. Antibodies to flagellin indicate reactivity to bacterial antigens in IBS patients. Neurogastroenterol Motil 2008; 20:1110-8. [PMID: 18694443 DOI: 10.1111/j.1365-2982.2008.01166.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
One of the several possible causes of irritable bowel syndrome (IBS) is thought to be low-grade mucosal inflammation. Flagellin, the primary structural component of bacterial flagellae, was shown in inflammatory bowel disease patients to activate the innate and adaptive immunity. It has not yet been conclusively established if IBS patients show reactivity to luminal antigens. In 266 patients [112 IBS, 61 Crohn's disease (CD), 50 ulcerative colitis (UC) and 43 healthy controls (HC)], we measured antibodies to flagellin (FAB, types A4-Fla2 and Fla-X), anti-Saccharomyces cerevisiae antibodies (ASCA) (both ELISA), antipancreas antibodies (PAB) and perinuclear antineutrophil cytoplasmatic antibodies (p-ANCA) (both IF). All IBS patients had normal fecal calprotectin (mean 21 microg mL(-1), SD 6.6) and fulfilled the ROME II criteria. Frequencies of antibodies in patients with IBS, CD, UC and HC, respectively, are as follows (in per cent): antibodies against A4-Fla2: 29/48/8/7; antibodies against Fla-X: 26/52/10/7; ASCA: 6/59/0/2; p-ANCA: 0/10/52/0; and PAB: 0/28/0/0. Antibodies against A4-Fla2 and Fla-X were significantly more frequent in IBS patients than in HC (P = 0.004 and P = 0.009). Antibodies to A4-Fla2 and Fla-X were significantly more frequent in IBS patients with antecedent gastroenteritis compared to non-postinfectious IBS patients (P = 0.002 and P = 0.012). In contrast to ASCA, PAB and p-ANCA, antibodies against A4-Fla2 and Fla-X were found significantly more often in IBS patients, particularly in those with postinfectious IBS, compared to HC. This observation supports the concept that immune reactivity to luminal antigens has a putative role in the development of IBS, at least in a subset of patients.
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Affiliation(s)
- A M Schoepfer
- Department of Gastroenterology, Inselspital, Bern University Hospital, Bern, Switzerland.
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26
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Shorbagi A, Bayraktar Y. Primary sclerosing cholangitis - What is the difference between east and west? World J Gastroenterol 2008; 14:3974-81. [PMID: 18609680 PMCID: PMC2725335 DOI: 10.3748/wjg.14.3974] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, progressive, cholestatic liver disease characterized by inflammation and fibrotic obliteration of the hepatic biliary tree. It is commonly associated with inflammatory bowel disease (IBD). A number of complications can occur which require special consideration, the most important of which is the development of cholangiocellular carcinoma (CCC). Unfortunately, no medical therapy is currently available for the underlying liver disease. Liver transplantation is an effective, life-extending option for patients with advanced PSC. Geographical variations between East and West include a second peak for age with a lower association with IBD in a Japanese population and female predominance in a lone study from Turkey. The clinical and biochemical Mayo criteria may not be universally applicable, as different patients show variations regarding the initial presentation and natural course of the disease. Directing research towards explaining these geographical differences and understanding the pathogenesis of PSC is required in order to develop better therapies for this devastating disease.
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27
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Morisco F, Pagliaro L, Caporaso N, Bianco E, Sagliocca L, Fargion S, Smedile A, Salvagnini M, Mele A. Consensus recommendations for managing asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels: suggestions for diagnostic procedures and monitoring. Dig Liver Dis 2008; 40:585-98. [PMID: 18395501 DOI: 10.1016/j.dld.2008.02.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2007] [Revised: 12/29/2007] [Accepted: 02/01/2008] [Indexed: 02/08/2023]
Abstract
A persistent increase in non-virus non-alcohol related aminotransferase levels can have multiple causes, which differ in terms of prevalence and clinical importance. In the general population, the most frequent cause is non-alcoholic hepatic steatosis, which can evolve into steato-hepatitis and cirrhosis. The treatment for steatosis and non-alcoholic steato-hepatitis consists of modifying lifestyles, whereas the effectiveness of drug treatment remains to be determined. Other much less frequent (yet not rare) causes of persistent non-virus non-alcohol related elevations in aminotransferase levels are celiac disease and hemochromatosis, whereas autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and alpha-1-anti-trypsin deficit are rare. Given that some of these conditions are susceptible to treatment, early diagnosis is important. No epidemiological data are available for evaluating the prevalence of elevated aminotransferase levels correlated with the toxicity of drugs or other xenobiotics, including herbal products. The present document, created by a panel of experts based on a systematic review of scientific evidence, is mainly geared towards physicians working in General Medicine and Transfusion Centres, who generally represent the first contact of persons with elevated aminotransferase levels. The document includes suggestions for diagnosing causes of persistent non-virus non-alcohol related increases in aminotransferase levels, considering the frequency and response to treatment. The conditions requiring specialized visits are also indicated.
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Affiliation(s)
- F Morisco
- Department of Food Science, University of Naples Federico II, Italy
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28
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Abstract
The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients, but the specificity of these antibodies is generally low, and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecific dysregulation of the immune system, but the literature in PSC points to the possible presence of specific antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC, with a particular emphasis on the prevalence, clinical relevance and possible pathogenetic importance of each individual marker.
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease. Associations with inflammatory bowel disease (IBD) especially ulcerative colitis (UC), and with particular autoimmune diseases, as well as the genetic associations further suggest PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease. PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.
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30
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Schoepfer AM, Trummler M, Seeholzer P, Seibold-Schmid B, Seibold F. Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis 2008; 14:32-9. [PMID: 17924558 DOI: 10.1002/ibd.20275] [Citation(s) in RCA: 193] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Symptoms of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) can overlap. We aimed to determine the accuracy of fecal markers, C-reactive protein (CRP), blood leukocytes, and antibody panels for discriminating IBD from IBS and to define a "best test." METHODS We prospectively included 64 patients with IBD (36 Crohn's disease [CD], 28 ulcerative colitis [UC]), 30 with IBS, and 42 healthy controls. Besides CRP and blood leukocytes, blinded fecal samples were measured for calprotectin (PhiCal Test, enzyme-linked immunosorbent assay [ELISA]), lactoferrin (IBD-SCAN, ELISA), Hexagon-OBTI (immunochromatographic test for detection of human hemoglobin), and LEUKO-TEST (lactoferrin latex-agglutination test). Blinded serum samples were measured for the antibodies ASCA (ELISA) and pANCA (immunofluorescence). RESULTS Overall accuracy of tests for discriminating IBD from IBS: IBD-SCAN 90%, PhiCal Test 89%, LEUKO-TEST 78%, Hexagon-OBTI 74%, CRP 73%, blood leukocytes 63%, CD antibodies (ASCA+/pANCA- or ASCA+/pANCA+) 55%, UC antibodies (pANCA+/ASCA-) 49%. ASCA and pANCA had an accuracy of 78% for detecting CD and 75% for detecting UC, respectively. The overall accuracy of IBD-SCAN and PhiCal Test combined with ASCA/pANCA for discriminating IBD from IBS was 92% and 91%, respectively. CONCLUSIONS The PhiCal Test and IBD-SCAN are highly accurate for discriminating IBD from IBS. There is only marginal additional diagnostic accuracy when the PhiCal Test and IBD-SCAN are combined with ASCA and pANCA. ASCA and pANCA have a high specificity for IBD.
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Affiliation(s)
- Alain M Schoepfer
- Department of Gastroenterology, Inselspital/University of Bern, Switzerland.
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31
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Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology 2007; 133:1670-89. [PMID: 17983810 DOI: 10.1053/j.gastro.2007.09.001] [Citation(s) in RCA: 290] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2007] [Accepted: 08/30/2007] [Indexed: 02/06/2023]
Abstract
The diagnosis of inflammatory bowel disease (IBD) with its 2 main subforms, Crohn's disease and ulcerative colitis, is based on clinical, endoscopic, radiologic, and histologic criteria. This paradigm remains unchanged despite the advent of new molecular technologies for the examination of serum proteins and genetic sequences, respectively. The main innovations in diagnostic technologies include the development of more sophisticated endoscopic and noninvasive imaging techniques with the aim of improving the identification of complications, in particular malignant diseases associated with IBD. The future will see further progress in the identification of genetic susceptibility factors and of protein biomarkers and their use to describe the molecular epidemiology of IBD. It can be expected that future diagnostic algorithms will include molecular parameters to detect early disease or guide therapies by predicting the individual course of disease.
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Affiliation(s)
- Susanna Nikolaus
- Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
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32
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Papp M, Norman GL, Altorjay I, Lakatos PL. Utility of serological markers in inflammatory bowel diseases: gadget or magic? World J Gastroenterol 2007; 13:2028-2036. [PMID: 17465443 PMCID: PMC4319120 DOI: 10.3748/wjg.v13.i14.2028] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2007] [Revised: 03/02/2007] [Accepted: 03/12/2007] [Indexed: 02/06/2023] Open
Abstract
The panel of serologic markers for inflammatory bowel diseases (IBD) is rapidly expanding. Although anti-Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) remain the most widely investigated, an increasing amount of experimental data is available on newly discovered antibodies directed against various microbial antigens. The role of the assessment of various antibodies in the current IBD diagnostic algorithm is often questionable due to their limited sensitivity. In contrast, the association of serologic markers with disease behavior and phenotype is becoming increasingly well-established. An increasing number of observations confirms that patients with Crohn's disease expressing multiple serologic markers at high titers are more likely to have complicated small bowel disease (e.g. stricture and/or perforation) and are at higher risk for surgery than those without, or with low titers of antibodies. Creating homogenous disease sub-groups based on serologic response may help develop more standardized therapeutic approaches and may help in a better understanding of the pathomechanism of IBD. Further prospective clinical studies are needed to establish the clinical role of serologic tests in IBD.
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Worthington J, Chapman R. Primary sclerosing cholangitis. Orphanet J Rare Dis 2006; 1:41. [PMID: 17062136 PMCID: PMC1636629 DOI: 10.1186/1750-1172-1-41] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2006] [Accepted: 10/24/2006] [Indexed: 12/18/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology characterised by inflammation and fibrosis of the biliary tree. The mean age at diagnosis is 40 years and men are affected twice as often as women. There is a reported annual incidence of PSC of 0.9-1.31/100,000 and point prevalence of 8.5-13.6/100,000. The onset of PSC is usually insidious and many patients are asymptomatic at diagnosis or have mild symptoms only such as fatigue, abdominal discomfort and pruritus In late stages, splenomegaly and jaundice may be a feature. In most, the disease progresses to cirrhosis and liver failure. Cholangiocarcinoma develops in 8-30% of patients. PSC is thought to be immune mediated and is often associated with inflammatory bowel disease, especially ulcerative colitis. The disease is diagnosed on typical cholangiographic and histological findings and after exclusion of secondary sclerosing cholangitis. Median survival has been estimated to be 12 years from diagnosis in symptomatic patients. Patients who are asymptomatic at diagnosis, the majority of whom will develop progressive disease, have a survival rate greater than 70% at 16 years after diagnosis. Liver transplantation remains the only effective therapeutic option for patients with end-stage liver disease from PSC, although high dose ursodeoxycholic acid may have a beneficial effect.
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Affiliation(s)
- Joy Worthington
- Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
| | - Roger Chapman
- Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
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Moritoki Y, Lian ZX, Ohsugi Y, Ueno Y, Gershwin ME. B cells and autoimmune liver diseases. Autoimmun Rev 2006; 5:449-57. [PMID: 16920571 DOI: 10.1016/j.autrev.2006.02.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2006] [Accepted: 02/16/2006] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the three major autoimmune diseases affecting the liver. They are all characterized by the presence of a variety of autoantibodies, some of which are found in all three diseases, whereas others are restricted to one or two of them or are even specific for the particular disease. In this review we will first provide details of the serological features of these three autoimmune diseases that target the liver. In addition, we will highlight the possible pathogenic roles of autoreactive B cells, focusing on their immunological functions as autoantibody producing cells and as antigen-presenting cells for T cell priming. As well, we will describe the contribution of toll-like receptor (TLR) signaling to the activation of autoimmune B cells and the putative role of defects in regulatory T cell function in the development of autoimmune liver diseases.
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Affiliation(s)
- Yuki Moritoki
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 E. Health Sciences Drive, Suite 6510, Davis, CA 95616, USA
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Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol 2006. [PMID: 15879616 DOI: 10.1385/criai: 28: 2: 093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology;however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease--especially ulcerative colitis--and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.
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Affiliation(s)
- Joy Worthington
- Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, UK
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Abstract
Inflammatory bowel disease (IBD) is an enduring disease involving mostly young people, with symptoms of bloody diarrhea and abdominal cramps. Several antibodies have been associated with IBD, the 2 most comprehensively studied being autoantibodies to neutrophils (atypical perinuclear anti-neutrophil cytoplasmic antibodies) and anti-Saccharomyces cerevisiae antibodies. This review focuses on the value of these antibodies for diagnosing IBD, differentiating Crohn disease from ulcerative colitis, indeterminate colitis, monitoring disease, defining clinical phenotypes, predicting response to therapy, and as subclinical markers. Pancreatic antibodies and newly identified anti-microbial antibodies (anti-outer membrane porin C, anti-I2, and anti-flagellin) are also reviewed.
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Affiliation(s)
- Xavier Bossuyt
- Laboratory Medicine, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.
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Abstract
Primary sclerosing cholangitis (PSC) is a fibrosing disease of the intra- and extra-hepatic bile ducts, and is closely associated with inflammatory bowel disease. It is immune mediated, rather than being a classical autoimmune disease. A range of immune abnormalities have been demonstrated in PSC, in particular the findings of a range of autoantibodies, a portal tract infiltrate of functional T cells, a restricted T-cell receptor repertoire, and aberrant expression of HLA molecules on biliary epithelial cells. The immunogenetics of PSC is currently under study and to date 4 key HLA haplotypes associated with PSC have been developed. The trigger factor for the initiation of the immune response may be the ingress of bacteria or other toxic metabolites into the portal circulation through a diseased and permeable bowel wall.
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Affiliation(s)
- Sue Cullen
- Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
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Smyth C, Kelleher D, Keeling PWN. Hepatic manifestations of gastrointestinal diseases. Inflammatory bowel disease, celiac disease, and Whipple's disease. Clin Liver Dis 2002; 6:1013-32. [PMID: 12516204 DOI: 10.1016/s1089-3261(02)00055-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gastrointestinal tract and the liver are closely related anatomically, physiologically, and pathologically. Some disease associations are well documented, such as PSC in association with IBD, whereas others are less well defined. A heightened clinical suspicion is required in these patients who do not present with the classical disease associations. The underlying causes of their diseases are the subject of much debate and research, and their diagnosis and management remain challenging.
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Affiliation(s)
- Claire Smyth
- Department of Clinical Medicine, Trinity College, Trinity Health Sciences Building, St. James Hospital, Dublin 8, Ireland.
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Rodríguez R, Zapata E, Esandi F, García-Bengoechea M, Torrado J, Castiella A. [Primary sclerosing cholangitis as a cause of hypertransaminasemia]. GASTROENTEROLOGIA Y HEPATOLOGIA 2002; 25:576-577. [PMID: 12435312 DOI: 10.1016/s0210-5705(02)70317-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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