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Cornillet M, Geanon D, Bergquist A, Björkström NK. Immunobiology of primary sclerosing cholangitis. Hepatology 2024:01515467-990000000-01014. [PMID: 39226402 DOI: 10.1097/hep.0000000000001080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, the presence of autoantibodies, the strong clinical link with inflammatory bowel disease, and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue residency and knowledge gained from novel technologies, including single-cell RNA sequencing and spatial transcriptomics. This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.
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Affiliation(s)
- Martin Cornillet
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel Geanon
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Unit of Gastroenterology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K Björkström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Shen B, Yao Q, Scherl EJ. Management of Primary Sclerosing Cholangitis and Extraintestinal Disorders in Patients With Ileal Pouches: A Systematic Review. Dis Colon Rectum 2024; 67:S106-S114. [PMID: 38411984 DOI: 10.1097/dcr.0000000000003231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
BACKGROUND Restorative proctocolectomy with IPAA improves the quality of life in patients with ulcerative colitis by the removal of diseased large bowel and preservation of the natural route of defecation. Although the surgery may improve preexisting extraintestinal manifestations in the joints, skin, and eyes, extraintestinal manifestations, particularly primary sclerosing cholangitis, can persist after colectomy. OBJECTIVES A systematic review of diagnosis and treatment of liver, joint, skin, and eye manifestations in patients with restorative proctocolectomy and IPAA for ulcerative colitis. DATA SOURCES PubMed, Google Scholar, and Cochrane database. STUDY SELECTION Relevant articles on primary sclerosing cholangitis and extraintestinal manifestations in ileal pouches published between January 2001 and July 2023 in English were included on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. INTERVENTION Diagnosis and treatment of primary sclerosing cholangitis and extraintestinal manifestations in patients with restorative proctocolectomy and IPAA were included. MAIN OUTCOME MEASURES Association between primary sclerosing cholangitis, extraintestinal manifestations, and inflammatory disorders of the pouch and their management. RESULTS Primary sclerosing cholangitis and extraintestinal manifestations are associated with pouchitis, particularly chronic pouchitis. Primary sclerosing cholangitis is associated with chronic pouchitis, enteritis, and possible pouch neoplasia. However, the disease severity and course of primary sclerosing cholangitis and pouchitis do not appear to be parallel. Despite the fact that oral vancomycin or budesonide have been used to treat primary sclerosing cholangitis-associated pouchitis, their impact on the disease course of primary sclerosing cholangitis is not known. Biological therapy for chronic inflammatory disorders of the pouch may also be beneficial for the concurrent extraintestinal manifestations of the joints, skin, and eyes. However, studies on the correlation between the severity of inflammatory pouch disorders and the severity of joint, skin, and eye diseases are lacking. LIMITATIONS This is a qualitative, not quantitative, review of case series and case reports. CONCLUSIONS Primary sclerosing cholangitis and extraintestinal manifestations of the joints, skin, and eyes appear to be associated with inflammatory disorders of the ileal pouch. Although the treatment of pouchitis does not seem to affect the disease course of primary sclerosing cholangitis, effective therapy of inflammatory pouch disorders, particularly with biologics, likely benefits concurrent disorders of the joints, skin, and eyes. See video from the symposium .
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Affiliation(s)
- Bo Shen
- Center for Inflammatory Bowel Disease, Columbia University Irving Medical Center/NewYork Presbyterian Hospital, New York, New York
| | - QingPing Yao
- Division of Rheumatology, Allergy and Immunology, Stony Brook University Renaissance School of Medicine, New York
| | - Ellen J Scherl
- Division of Gastroenterology and Hepatology, Department of Medicine, New York-Presbyterian/Weill Cornell Medical Center, New York, New York
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Tilg H, Adolph TE, Tacke F. Therapeutic modulation of the liver immune microenvironment. Hepatology 2023; 78:1581-1601. [PMID: 37057876 DOI: 10.1097/hep.0000000000000386] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/14/2023] [Indexed: 04/15/2023]
Abstract
Inflammation is a hallmark of progressive liver diseases such as chronic viral or immune-mediated hepatitis, alcohol-associated liver disease, and NAFLD. Preclinical and clinical studies have provided robust evidence that cytokines and related cellular stress sensors in innate and adaptive immunity orchestrate hepatic disease processes. Unresolved inflammation and liver injury result in hepatic scarring, fibrosis, and cirrhosis, which may culminate in HCC. Liver diseases are accompanied by gut dysbiosis and a bloom of pathobionts, fueling hepatic inflammation. Anti-inflammatory strategies are extensively used to treat human immune-mediated conditions beyond the liver, while evidence for immunomodulatory therapies and cell therapy-based strategies in liver diseases is only emerging. The development and establishment of novel immunomodulatory therapies for chronic liver diseases has been dampened by several clinical challenges, such as invasive monitoring of therapeutic efficacy with liver biopsy in clinical trials and risk of DILI in several studies. Such aspects prevented advancements of novel medical therapies for chronic inflammatory liver diseases. New concepts modulating the liver immune environment are studied and eagerly awaited to improve the management of chronic liver diseases in the future.
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Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
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Efficacy and safety of immune-modulating therapy for primary sclerosing cholangitis: A systematic review and meta-analysis. Pharmacol Ther 2022; 237:108163. [DOI: 10.1016/j.pharmthera.2022.108163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 11/17/2022]
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Dervout C, Boulais N, Barnetche T, Nousbaum JB, Brenaut E, Misery L. Efficacy of Treatments for Cholestatic Pruritus: A Systemic Review and Meta-analysis. Acta Derm Venereol 2022; 102:adv00653. [PMID: 35088869 PMCID: PMC9609979 DOI: 10.2340/actadv.v102.310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestatic itch is a disabling symptom that may be secondary to liver or biliary diseases. Management of cholestatic pruritus is complex. A systematic review and meta-analysis on the efficacy of treatments for cholestatic pruritus were performed. PubMed and Cochrane Library were searched using the algorithm “(hepatitis OR cholestatic OR liver) AND (pruritus OR itch) AND (management OR treatment OR treatments)” for 1975–2019. Of the 2,264 articles identified, 93 were included in a systematic review and 15 in a meta-analysis (studies evaluating pruritus with a visual analogue scale). Some treatments act by reducing levels of pruritogens in the enterohepatic cycle, others modify the metabolism or secretion of these pruritogens, or act on pruritus pathways. A further possible treatment is albumin dialysis. However, due to many heterogeneities in the reviewed studies it is difficult to identify and recommend an optimum treatment. Only 15 studies were included in the meta-analysis, due to the small number of randomized studies using a visual analogue scale.
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Affiliation(s)
| | | | | | | | - Emilie Brenaut
- Department of Dermatology, University Hospital, FR-29609 Brest, France.
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Abstract
Biliary strictures have several etiologies that can broadly be classified into benign and malignant causes. The clinical presentation is variable with strictures identified incidentally on imaging or during the evaluation of routine laboratory abnormalities. Symptoms and cholangitis lead to imaging that can diagnose biliary strictures. The diagnosis and medical management of biliary strictures will be discussed in this article.
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Affiliation(s)
- Terrance Rodrigues
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Justin R Boike
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Mago S, Wu GY. Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis Overlap Syndrome: A Review. J Clin Transl Hepatol 2020; 8:336-346. [PMID: 33083257 PMCID: PMC7562796 DOI: 10.14218/jcth.2020.00036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/21/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are slow progressive diseases which have been increasing in prevalence. The pathogeneses of PBC and PSC are incompletely understood but the underlying mechanisms appear to be fundamentally autoimmune in origin. Although PBC and PSC appear to be separate entities, overlap has been described. Diagnosis depends on a combination of serological markers, imaging, and pathological criteria. The mainstay of treatment has been ursodeoxycholic acid and in some cases of extrahepatic biliary obstruction and overlap disorder, endoscopic retrograde cholangiopancreatography has been useful.
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Affiliation(s)
- Sheena Mago
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Sheena Mago, Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Kalani A, Tabibian JH, Lindor KD. Emerging therapeutic targets for primary sclerosing cholangitis. Expert Opin Orphan Drugs 2018; 6:393-401. [DOI: 10.1080/21678707.2018.1490643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Amir Kalani
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Gastroenterology Fellowship Training Program, Los Angeles, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
| | - Keith D. Lindor
- Professor of Medicine and Senior Advisor to the Provost, College of Health Solutions, Arizona State University, USA
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Chen JH, Deshpande V. Inflammatory Nodules Identify Steroid-Responsive Primary Sclerosing Cholangitis. Int J Surg Pathol 2018; 26:402-409. [PMID: 29464971 DOI: 10.1177/1066896918758451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a cholangiopathy-usually associated with inflammatory bowel disease-that leads to cirrhosis and liver failure. Based on a multitude of clinical trials, there is general consensus that PSC progression is unchanged by current therapies, including steroids. However, there are scattered reports in the literature of PSC patients responsive to steroids. Recently, several steroid-responsive PSC mimics have been described, most notably immunoglobulin G4-related sclerosing cholangitis. Following these discoveries, many assume that cases in the literature previously reported as steroid-responsive PSC would now be classified as one of these mimics. We reviewed liver biopsies and the medical histories of patients diagnosed with PSC with documented response to steroids. We identified 3 cases of steroid-responsive PSC in patients with inflammatory bowel disease that do not fit criteria of known PSC mimics. All 3 were adults (age range = 18-44 years) with inflammatory bowel disease, and included 2 males and 1 female. All 3 patients had abnormal liver function tests that normalized on prednisone. Histologically, these 3 cases share a common feature, hepatic fibroinflammatory nodules in a collagen-rich background. They lacked clinical, serologic, and histologic features of immunoglobulin G4-related sclerosing cholangitis. These cases suggest that fibroinflammatory nodules may identify a unique subset of PSC patients who are responsive to steroids.
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Affiliation(s)
- Jonathan H Chen
- 1 Massachusetts General Hospital, Boston, MA, USA.,2 Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- 1 Massachusetts General Hospital, Boston, MA, USA.,2 Harvard Medical School, Boston, MA, USA
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Petrescu AD, Grant S, Frampton G, Kain J, Hadidi K, Williams E, McMillin M, DeMorrow S. Glucocorticoids Cause Gender-Dependent Reversal of Hepatic Fibrosis in the MDR2-Knockout Mouse Model. Int J Mol Sci 2017; 18:E2389. [PMID: 29125588 PMCID: PMC5713358 DOI: 10.3390/ijms18112389] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/06/2017] [Accepted: 11/06/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatic cholestasis is associated with a significant suppression of the hypothalamus-pituitary-adrenal axis (HPA). In the present study, we tested the hypothesis that activation of the HPA axis by corticosterone treatment can reverse liver inflammation and fibrosis in a multidrug resistance protein 2 knockout (MDR2KO) transgenic mouse model of hepatic cholestasis. Friend Virus B NIH-Jackson (FVBN) control and MDR2KO male and female mice were treated with vehicle or corticosterone for two weeks, then serum and liver analyses of hepatic cholestasis markers were performed. Indicators of inflammation, such as increased numbers of macrophages, were determined. MDR2KO mice had lower corticotropin releasing hormone and corticosterone levels than FVBN controls in the serum. There was a large accumulation of CD68 and F4/80 macrophages in MDR2KO mice livers, which indicated greater inflammation compared to FVBNs, an effect reversed by corticosterone treatment. Intrahepatic biliary duct mass, collagen deposition and alpha smooth muscle actin (αSMA) were found to be much higher in livers of MDR2KO mice than in controls; corticosterone treatment significantly decreased these fibrosis markers. When looking at the gender-specific response to corticosterone treatment, male MDR2KO mice tended to have a more pronounced reversal of liver fibrosis than females treated with corticosterone.
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Affiliation(s)
- Anca D Petrescu
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Stephanie Grant
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Gabriel Frampton
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Jessica Kain
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Karam Hadidi
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Elaina Williams
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
| | - Matthew McMillin
- Central Texas Veterans Health Care System, Temple, TX 76504, USA.
| | - Sharon DeMorrow
- Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA.
- Central Texas Veterans Health Care System, Temple, TX 76504, USA.
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Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study. Inflamm Bowel Dis 2017; 23:1174-1181. [PMID: 28452862 DOI: 10.1097/mib.0000000000001109] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Extraintestinal manifestations (EIMs) in patients with inflammatory bowel disease (IBD) are frequently observed. Little is known about the efficacy of anti-tumor necrosis factor (TNF) in EIM management. We assessed the effect of 3 anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) on EIM evolution. METHODS Data on 1249 patients from the Swiss IBD Cohort Study (SIBDCS) were analyzed. All EIMs were diagnosed by relevant specialists. Response was classified into improvement, stable disease, and clinical worsening based on the physician's interpretation. RESULTS Of the 366 patients with at least 1 EIM, 213 (58.2%) were ever treated with an anti-TNF. A total of 299 treatments were started for 355 EIMs. Patients with EIM were significantly more often treated with anti-TNF compared with those without EIM (58.2% versus 21.0%, P < 0.001). Infliximab was the most frequently used drug (63.2%). In more than 71.8%, a clinical response of the underlying EIM to anti-TNF therapy was observed. In 92 patients (43.2%), anti-TNF treatments were started for the purpose of treating EIM rather than IBD. Response rates to anti-TNF were generally good and best for psoriasis, aphthous stomatitis, uveitis, and peripheral arthritis. In 11 patients, 14 EIM occurred under anti-TNF treatment. CONCLUSIONS Anti-TNF was frequently used among patients with EIM. In more than 40%, anti-TNF treatments are started to treat EIM rather than IBD. Given the good response rates, anti-TNF seems to be a valuable option in the treatment of EIM, whereas appearance of EIM under anti-TNF does not seem to be a source of considerable concern.
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12
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Goode EC, Rushbrook SM. A review of the medical treatment of primary sclerosing cholangitis in the 21st century. Ther Adv Chronic Dis 2016; 7:68-85. [PMID: 26770670 DOI: 10.1177/2040622315605821] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that progresses to end-stage liver disease and cirrhosis. Recurrent biliary inflammation is thought to lead to dysplasia, and as such PSC confers a high risk of cholangiocarcinoma. PSC accounts for 10% of all UK liver transplants, although transplantation does not guarantee a cure with 20% recurrence in the graft. At present there are no effective medical treatment options for PSC, and trials of novel therapeutic agents are limited by the time taken to reach clinically significant endpoints with no well defined early surrogate markers for disease outcome. Moreover, PSC appears to be a heterogeneous disease with regards to disease distribution, associated inflammatory bowel disease and subsequent disease outcome, further compounding the issue. Thus existing trials have taken place in heterogeneous groups, are likely to be underpowered to detect any individual subgroups effect. The current mainstay of medical treatment is still with ursodeoxycholic acid, although there is no evidence that it alters long-term outcome. Small pilot studies of immunosuppressive agents have taken place, but despite evidence that may support studies in larger groups, these have not been conducted. Recent advances in our understanding of the disease pathogenesis may therefore pave the way for trials of novel therapeutic agents in PSC, even given the limitations described. This review explores the controversial evidence underlying current treatment strategies and discounted treatments, and explores prospective agents that may bring new hope to the treatment of PSC in the 21st century.
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Affiliation(s)
- Elizabeth C Goode
- Department of Hepatology, Norfolk and Norwich University Hospital, Norwich, UK
| | - Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK
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Ali AH, Carey EJ, Lindor KD. An overview of current and future therapeutic strategies for the treatment of primary sclerosing cholangitis. Expert Opin Orphan Drugs 2014. [DOI: 10.1517/21678707.2014.908701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Abstract
Primary sclerosing cholangitis is the classic hepatobiliary manifestation of inflammatory bowel disease and is generally chronic and progressive. Patients frequently present with asymptomatic, anicteric cholestasis, but many develop progressive biliary strictures with time, leading to recurrent cholangitis, biliary cirrhosis, and end-stage liver disease. Medical treatment does not slow the progression of disease, and many patients need liver transplantation, after which recurrent disease is a risk. The increased incidence of hepatobiliary cancer, which is not related to the underlying severity of biliary fibrosis, is of particular concern. Risk of colorectal cancer is also increased in patients with coexistent inflammatory bowel disease. Mechanistic insights have arisen from studies of secondary sclerosing cholangitis, in which a similar clinical profile is associated with a specific cause, and genomic studies have elucidated potential disease-initiating pathways in the primary form. The close association between inflammatory bowel disease and primary sclerosing cholangitis underscores the need to further understand the role of environmental factors in generation of lymphocytes that are postulated to be retargeted, deleteriously, to the biliary tree. Treatment of primary sclerosing cholangitis is confined to supportive measures, but advances in pathobiology suggest that new stratified approaches will soon be available.
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Affiliation(s)
- Gideon M Hirschfield
- Centre for Liver Research, National Institute for Health Research Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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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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Kim JH, Byun JH, Kim SY, Lee SS, Kim HJ, Kim MH, Lee MG. Sclerosing cholangitis with autoimmune pancreatitis versus primary sclerosing cholangitis: comparison on endoscopic retrograde cholangiography, MR cholangiography, CT, and MRI. Acta Radiol 2013; 54:601-7. [PMID: 23528564 DOI: 10.1177/0284185113481018] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) from primary sclerosing cholangitis (PSC) as the treatment and prognosis of the two diseases are totally different. PURPOSE To compare image findings of SC-AIP and PSC on endoscopic retrograde cholangiography (ERC), magnetic resonance cholangiography (MRC), computed tomography (CT), and magnetic resonance imaging (MRI). MATERIAL AND METHODS Two radiologists retrospectively reviewed ERC, MRC, CT, and MRI in 28 SC-AIP and 23 PSC patients in consensus. Factors evaluated included the length, location, and multiplicity of bile duct stricture, the presence of characteristic cholangiographic features of PSC on ERC and MRC, and the presence, location, thickness, and pattern of bile duct wall thickening on CT and MRI. RESULTS On ERC, focal stricture, multifocal and intrahepatic bile duct stricture, and beaded, pruned-tree, and diverticulum-like appearance were more frequent in PSC than in SC-AIP patients (P ≤ 0.006). On MRC, multifocal and intrahepatic bile duct stricture and pruned-tree appearance were more frequent in PSC than in SC-AIP patients (P ≤ 0.044). On CT and MRI, the bile duct wall was thicker (5.1 mm vs. 3.1 mm; P = 0.033 and 4.3 mm vs. 3.0 mm; P = 0.01, respectively) in SC-AIP than in PSC patients. PSC was more frequently associated with intrahepatic bile duct wall thickening on both CT (93% vs. 50%; P = 0.024) and MRI (100% vs. 50%; P = 0.023) than SC-AIP. CONCLUSION The combination of ERC or MRC with cross-sectional images, including CT and MRI, may be helpful in differentiating between SC-AIP and PSC.
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Affiliation(s)
- Jin Hee Kim
- Department of Radiology and Research Institute of Radiology
| | - Jae Ho Byun
- Department of Radiology and Research Institute of Radiology
| | - So Yeon Kim
- Department of Radiology and Research Institute of Radiology
| | - Seung Soo Lee
- Department of Radiology and Research Institute of Radiology
| | | | - Myung-Hwan Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Moon-Gyu Lee
- Department of Radiology and Research Institute of Radiology
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Urosdeoxycholic acid in primary sclerosing cholangitis: a meta-analysis and systematic review. Arab J Gastroenterol 2012; 13:103-10. [PMID: 23122450 DOI: 10.1016/j.ajg.2012.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 02/23/2012] [Accepted: 06/10/2012] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND STUDY AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with no proven effective medical therapy. Ursodeoxycholic acid (UDCA) was proposed as a potential treatment for this disorder. However, several randomised controlled trials reported conflicting results regarding the usefulness of UDCA. The aim of this meta-analysis and systematic review is to investigate the efficacy of UDCA in PSC. PATIENTS AND METHODS Literature review was performed to include randomised controlled trials and non-randomised studies comparing UDCA to a placebo in PSC. The included controlled trials were assigned a quality score. Random effects model was used. Outcomes were measured with Weight Mean Difference, Risk Ratio or Risk Difference. Heterogeneity was measured by I(2) measure of inconsistency. RESULTS Seven RCTs satisfied the inclusion criteria with a total number of 553 patients. Low dose UDCA was used in 4 studies, high dose UDCA (17-30mg/kg) was used in three studies. UDCA did not decrease the risk of mortality compared to placebo (RR=1.04, 95% CI 0.46-2.35) or the need for liver transplant (RR=1.22, 95% CI 0.7-2.12). UDCA also had no effect on the clinical symptoms. Liver Function Tests (LFTs) were significantly improved in the UDCA treated patients. UDCA did not decrease the incidence of cholangiocarcinoma. CONCLUSION UDCA had no beneficial effect on the patients' survival, liver histology, prevention of cholangiocarcinoma, or improvement of clinical symptoms. High dose UDCA was associated with increased mortality in one of the large randomised trial included in this analysis.
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is associated with considerable morbidity and mortality. The disease etiopathogenesis has not been well defined. Several observations suggest that portal bacteremia or chronic bile duct infection may be factors that could play a role in the pathogenesis of the disease. Clinical trials have tested different treatments for PSC but without convincing evidence of benefit. Liver transplantation is the only available therapeutic option that is thought to be beneficial for PSC. Antibiotics have been used in several case series over the years to treat PSC and have had, in some cases, impressive benefits when compared with other drugs used for treating the disease. We gathered the available data for different antibiotics used in PSC in this review. Further studies are needed to support the efficacy of using antibiotics for PSC patients.
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Affiliation(s)
- Diaa Aldin H Elfaki
- Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN 55901, USA
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Culver EL, Chapman RW. Systematic review: management options for primary sclerosing cholangitis and its variant forms - IgG4-associated cholangitis and overlap with autoimmune hepatitis. Aliment Pharmacol Ther 2011; 33:1273-91. [PMID: 21501198 DOI: 10.1111/j.1365-2036.2011.04658.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) remains a challenging disease to manage. The main goals are prevention of disease progression and reduction of the increased cancer risk. AIMS To review the management strategies for PSC and its variant forms based on published studies. METHODS Publications were identified using Pubmed, Medline and Ovid search engines. RESULTS Distinguishing PSC from variants, such as IgG4-associated cholangitis, and overlap with autoimmune hepatitis is essential to guide treatment decisions. There is no proven efficacious medical treatment for PSC. Ursodeoxycholic acid has been disappointing in low and moderate doses, and potentially dangerous in higher doses, although its role and optimal dose in chemoprevention requires investigation. The novel bile acid, 24-norursodeoxycholic acid, has shown promise in mouse models; human trials are in progress. Dominant strictures are optimally managed by dilatation and stenting to relieve obstructive complications, although exclusion of biliary malignancy is essential. Liver transplantation is the only proven therapy for those with advanced disease. Cholangiocarcinoma remains the most unpredictable and feared complication. In highly selected groups, neo-adjuvant chemoradiation with liver transplantation seems promising, but requires further validation. Screening for inflammatory bowel disease and surveillance for colorectal carcinoma should not be overlooked. CONCLUSIONS The effective management of PSC and its variants is hindered by uncertainties regarding pathogenesis of disease and factors responsible for its progression. Genome studies may help to identify further targets for drug therapy and factors leading to malignant transformation.
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Aljiffry M, Renfrew PD, Walsh MJ, Laryea M, Molinari M. Analytical review of diagnosis and treatment strategies for dominant bile duct strictures in patients with primary sclerosing cholangitis. HPB (Oxford) 2011; 13:79-90. [PMID: 21241424 PMCID: PMC3044341 DOI: 10.1111/j.1477-2574.2010.00268.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The diagnosis and treatment of indeterminate dominant strictures (DS) in patients with primary sclerosing cholangitis (PSC) is challenging and the literature on the subject is scarce. OBJECTIVES This review aims to appraise and synthesize the evidence published in the English-language medical literature on this topic. METHODS Scientific papers published from 1950 until week 4 of July 2010 were extracted from MEDLINE, Ovid Medline In-Process, the Cochrane Database of Systematic Reviews, the Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, EMBASE, PubMed and the National Library of Medicine Gateway. RESULTS Strategies for the optimal management of DS in PSC patients are supported only by level II and III evidence. Intraductal endoscopic ultrasound appears to be the most sensitive (64%) and specific (95%) diagnostic test for the evaluation of DS in PSC. Endoscopic and percutaneous dilatations achieve 1- and 3-year palliation in 80% and 60% of patients, respectively. Although dilatation and stenting are the most common palliative interventions in DS, no randomized trials on the optimal duration of treatment have been conducted. CONCLUSIONS In benign DS, endoscopic dilatation with short-term stenting seems to be effective and safe and does not increase the risks for malignant transformation or complications after liver transplantation. Surgical bile duct resection and/or bilioenteric bypass are indicated only in patients with preserved liver function.
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Affiliation(s)
- Murad Aljiffry
- Section of Hepatopancreaticobiliary and Transplant Surgery, McGill University Health CentreMontreal, Canada,Department of Surgery, College of Medicine, King Abdul Aziz UniversityJeddah, Saudi Arabia
| | - Paul D Renfrew
- Department of Surgery, Dalhousie University, Queen Elizabeth II Health Science CenterHalifax, NS, Canada
| | - Mark J Walsh
- Department of Surgery, Dalhousie University, Queen Elizabeth II Health Science CenterHalifax, NS, Canada
| | - Marie Laryea
- Department of Surgery, Dalhousie University, Queen Elizabeth II Health Science CenterHalifax, NS, Canada
| | - Michele Molinari
- Department of Surgery, Dalhousie University, Queen Elizabeth II Health Science CenterHalifax, NS, Canada
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Abstract
Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of intra-/extrahepatic bile ducts, leading to multifocal strictures. Primary sclerosing cholangitis exhibits a progressive course resulting in cirrhosis and the need for liver transplantation over a median period of 12 years. The disease is frequently associated with inflammatory bowel disease and carries an increased risk of colorectal cancer and cholangiocarcinoma. Despite extensive research, there is currently no effective medical treatment. Multiple drugs are shown to be ineffective in halting disease progression, including ursodeoxycholic acid, the most widely evaluated drug. High-dose ursodeoxycholic acid (28-30 mg/kg/day) was recently shown to increase the adverse events rate. Endoscopic or radiological dilatation of a 'dominant' stricture may lead to symptomatic and biochemical improvement. However, liver transplantation is the only life-prolonging treatment for patients with end-stage disease. Studies with promising drugs, such as antibiotics, antifibrotic agents and bile acid derivatives, are eagerly awaited.
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Affiliation(s)
- Emmanouil Sinakos
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA
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Koyabu M, Uchida K, Fukata N, Kusuda T, Ikeura T, Sakaguchi Y, Yoshida K, Shimatani M, Fukui T, Matsushita M, Uemura Y, Kaibori M, Takaoka M, Nishio A, Okazaki K. Primary sclerosing cholangitis with elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells. J Gastroenterol 2010; 45:122-9. [PMID: 19760481 DOI: 10.1007/s00535-009-0130-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Accepted: 08/19/2009] [Indexed: 02/04/2023]
Abstract
Immunoglobin G4-related sclerosing cholangitis (IgG4-SC) is recognized as one of the systemic sclerosing diseases characterized by abundant IgG4-positive plasma cells with effective steroid therapy. On the other hand, primary sclerosing cholangitis (PSC), recognized as a sclerosing cholangitis of unknown origin without steroid efficacy, has been often clinically confused with IgG4-SC. To date, the prognosis of IgG4-SC is unclear, while the prognosis of PSC is well known to be poor. Therefore, it is clinically very important to be able to distinguish IgG4-SC from PSC. However, at the present time it still remains unclear whether PSC may sometimes be misdiagnosed as IgG4-SC or not. Herein, we report three rare cases of PSC with elevated serum IgG4 levels and/or an infiltration of abundant IgG4-positive plasma cells in the liver: a young male with ulcerative colitis (UC), and elderly female and a young female, each with elevated serum IgG4 levels. The first two patients showed infiltration of abundant IgG4-positive plasma cells in the portal area of the liver without response to steroid therapy. From our experiences, we emphasize that some patients with PSC, who do not respond to steroid therapy, show elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells, although the mechanism still remains unclear.
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Affiliation(s)
- Masanori Koyabu
- The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Japan
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Beuers U, Kullak-Ublick GA, Pusl T, Rauws ER, Rust C. Medical treatment of primary sclerosing cholangitis: a role for novel bile acids and other (post-)transcriptional modulators? Clin Rev Allergy Immunol 2009; 36:52-61. [PMID: 18751930 DOI: 10.1007/s12016-008-8085-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether "high dose" UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregnane-X receptor (PXR), vitamin D receptor (VDR), and peroxisome-proliferator-activator receptors (PPARs) have been shown to induce expression of diverse carriers and biotransformation enzymes of the intestinal and hepatic detoxification machinery and/or to modulate fibrogenesis. Pros and cons of respective receptor agonists for the future treatment of PSC are discussed in detail. In our view, the novel bile acid norUDCA and agonists of PPARs, VDR, and PXR appear particularly attractive for further studies in PSC.
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Affiliation(s)
- Ulrich Beuers
- Department of Gastroenterology and Hepatology, G4-213, Academic Medical Center, University of Amsterdam, P. O. Box 22700, 1100, DE, Amsterdam, The Netherlands.
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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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Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur J Gastroenterol Hepatol 2008; 20:688-92. [PMID: 18679073 DOI: 10.1097/meg.0b013e3282f5197e] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Beneficial effects of probiotics have been reported in liver disease. Inflammatory bowel disease concurs in 90% of primary sclerosing cholangitis (PSC) patients, suggesting that substances originating from the inflamed gut may damage the biliary tree. OBJECTIVE To assess potential beneficial effects of probiotics on serum liver tests, pruritus and fatigue in PSC. METHODS Fourteen patients (13 male/one female, mean age 45 years), with concurrent inflammatory bowel disease were randomized to treatment with probiotics (Ecologic 641, containing four Lactobacillus and two Bifidobacillus strains; Winclove Bio Industries, Amsterdam, The Netherlands) or placebo during 3 months in a double-blind fashion. After a 1-month washout period, crossover was made. RESULTS No changes in pruritus, fatigue and stool frequency were noted during placebo or probiotics. No significant differences were observed between treatment with probiotics and placebo in bilirubin (at end of probiotic vs. placebo period: -13 vs. -15% change from baseline; P=0.89), alkaline phosphatase (-9 vs. -9%; P=0.99), gamma glutamyl transpeptidase (-11 vs. -5%; P=0.60), aspartate aminotransferase (-16 vs. -15%; P=0.99), alanine aminotransferase (-27 vs. -26%; P=0.97), prothrombin, albumin or bile salts. CONCLUSION Our data do not support beneficial effects of probiotics on symptoms, liver biochemistry or liver function in PSC.
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The challenges in primary sclerosing cholangitis--aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol 2008; 48 Suppl 1:S38-57. [PMID: 18304683 DOI: 10.1016/j.jhep.2008.01.020] [Citation(s) in RCA: 118] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by progressive inflammation and fibrosis of the bile ducts, resulting in biliary cirrhosis and is associated with a high risk of cholangiocarcinoma. The majority of patients are young, male and have coexisting inflammatory bowel disease. PSC is found with a prevalence of 10/100,000 in Northern European populations. The pathophysiology of PSC is a complex multistep process including immunological mechanisms, immunogenetic susceptibility and disorders of the biliary epithelia. The diagnosis is primarily based on endoscopic cholangiography although magnetic resonance imaging is increasingly used; biochemistry and immunoserology as well as histology play only a minor role. Due to the high risk of developing cholangiocarcinoma and also other tumours of the GI tract, surveillance strategies are essential, however they have yet to be established and evaluated. Biochemical parameters, clinical risk factors, endoscopic procedures and imaging techniques contribute to the early identification of patients at risk. Since medical therapy of PSC with ursodeoxycholic acid does not improve survival, to date, liver transplantation is the only option with a cure potential; if transplantation is accurately timed, transplanted PSC patients have an excellent rate of survival. However if cholangiocarcinoma is detected, a curative treatment is not possible in the majority of cases. The present review critically summarizes the current knowledge on the aetiopathogenesis of PSC and gives an overview of the diagnostic approaches, surveillance strategies and therapeutic options. Primary sclerosing cholangitis is a disease of unknown aetiology and without any further curative treatment options apart from liver transplantation. Therefore it may be regarded as the greatest challenge in hepatology today.
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Abstract
Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in cirrhosis and need for liver transplantation and reduced life expectancy. The majority of cases occur in young and middle-aged men, often in association with inflammatory bowel disease. The etiology of primary sclerosing cholangitis includes immune-mediated components and elements of undefined nature. No effective medical therapy has been identified. The multiple complications of primary sclerosing cholangitis include metabolic bone disease, dominant strictures, bacterial cholangitis, and malignancy, particularly cholangiocarcinoma, which is the most lethal complication of primary sclerosing cholangitis. Liver transplantation is currently the only life-extending therapeutic alternative for patients with end-stage disease, although recurrence in the allografted liver has been described. A PSC-like variant attracting attention is cholangitis marked by raised levels of the immunoglobulin G4 subclass, prominence of plasma cells within the lesions, and steroid responsiveness.
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver condition characterized by progressive fibrosis and destruction of the intra- and extrahepatic biliary tree. PSC has a clear association with inflammatory bowel disease and is often progressive, leading to cirrhosis and end-stage liver failure. For many patients, liver transplantation offers the only hope of long-term survival. No effective medical treatment exists, and therapy is often aimed at treating complications of the disorder, including dominant biliary strictures, which may cause symptomatic jaundice, cholangitis, and pruritus. Studies on endoscopic therapy (eg, biliary dilation and/or stent insertion) have shown favorable results, although most studies have been small, retrospective, and uncontrolled. Up to 20% of patients with PSC develop cholangiocarcinoma; however, distinguishing between cholangiocarcinoma and benign strictures can be difficult. Ideally, randomized trials are required to determine the safest and most effective endoscopic management for symptomatic dominant strictures.
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Affiliation(s)
- Mark McLoughlin
- Division of Gastroenterology, St Paul's Hospital, 1144 Burrard Street, Vancouver, British Columbia, Canada.
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30
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Hirano A, Nakazawa T, Ohara H, Ando T, Hayashi K, Tanaka H, Naito I, Okumura F, Yokoyama Y, Joh T. Liver atrophy and portal stenosis in two cases of sclerosing cholangitis associated with autoimmune pancreatitis. Intern Med 2008; 47:1689-94. [PMID: 18827417 DOI: 10.2169/internalmedicine.47.1192] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Sclerosing cholangitis with autoimmune pancreatitis (SC with AIP) takes a better clinical course than primary sclerosing cholangitis due to the effectiveness of steroid therapy. However, the morphological and functional changes in SC with AIP during long-term observation have not yet been reported. We encountered two cases of SC with AIP that resulted in liver atrophy and portal obstruction during long-term observation. One case was followed up without steroid therapy. The other case was treated with endoscopic biliary drainage initially. These cases may provide further information regarding steroid therapy for SC with AIP.
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Affiliation(s)
- Atsuyuki Hirano
- Department of Internal Medicine, Nagoya Higashi Municipal Hospital
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Nishino T, Oyama H, Hashimoto E, Toki F, Oi I, Kobayashi M, Shiratori K. Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis. J Gastroenterol 2007; 42:550-9. [PMID: 17653651 DOI: 10.1007/s00535-007-2038-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2006] [Accepted: 03/06/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND The present study was undertaken to identify the clinicopathological differences between sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) and primary sclerosing cholangitis (PSC). METHODS We retrospectively compared the clinical, cholangiographic, and liver biopsy findings between 24 cases of PSC and 24 cases of SC-AIP. RESULTS Patient age at the time of diagnosis was significantly lower in the PSC group than in the SC-AIP group. The peripheral blood eosinophil count was significantly higher in the PSC group than in the SC-AIP group, but the serum IgG4 level was significantly higher in the SC-AIP group. Cholangiography revealed band-like strictures, beaded appearance, and pruned-tree appearance significantly more frequently in PSC, whereas segmental strictures and strictures of the distal third of the common bile duct were significantly more common in SC-AIP. Liver biopsy revealed fibrous obliterative cholangitis only in the PSC specimens. No advanced fibrous change corresponding to Ludwig's stages 3 and 4 was observed in any of the SC-AIP specimens. IgG4-positive plasma cell infiltration of the liver was significantly more severe in SC-AIP than in PSC. Subsequent cholangiography showed no improvement in any of the PSC cases, but all SC-AIP patients responded to steroid therapy, and improvement in the strictures was observed cholangio-graphically. CONCLUSIONS Based on the differences between the patients' ages and blood chemistry, cholangiographic, and liver biopsy findings, SC-AIP should be differentiated from PSC.
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Affiliation(s)
- Takayoshi Nishino
- Institute of Gastroenterology, Department of Medicine, Tokyo Women's Medical University, School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Ohara H, Nakazawa T, Ando T, Joh T. Systemic extrapancreatic lesions associated with autoimmune pancreatitis. J Gastroenterol 2007; 42 Suppl 18:15-21. [PMID: 17520218 DOI: 10.1007/s00535-007-2045-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Autoimmune pancreatitis (AIP) is frequently associated with sclerosing cholangitis (SC). SC with AIP has a cholangiographic appearance that is often confused with primary sclerosing cholangitis (PSC) but only the former responds well to corticosteroid therapy. Detailed study of cholangiographic findings allows discrimination of SC with AIP from PSC. Band-like strictures, a beaded or pruned-tree appearance, and diverticulum-like outpouching were significantly more frequently observed in cases of PSC. In contrast, segmental strictures, dilation after confluent stricture, and strictures of the lower common bile duct were significantly more common in SC with AIP. The other systemic extrapancreatic lesions associated with AIP found in the literature were Sjögren's syndrome, ulcerative colitis, retroperitoneal fibrosis, sialadenitis, thyroiditis, and idiopathic thrombocytopenic purpura. In a comparison of the clinical course and laboratory data of our cases, gamma-globulin, IgG, and IgG4 levels were significantly higher in patients with AIP with systemic extrapancreatic lesions than those without them. In our immunohistochemical study, marked infiltration of IgG4+ plasma cells was frequently observed in the pancreas, liver, bile duct, and salivary glands of the AIP patients examined. In contrast, the degree of infiltration of IgG4+ plasma cells around the bile duct in the portal areas and the extrahepatic bile duct with PSC was significantly lower than with AIP. These results also suggest that AIP is a disease state clearly different from PSC. In addition, the normal epithelia of the pancreatic ducts, bile ducts, gallbladder, and salivary gland ducts reacting with the patients' sera was detectable by the anti-IgG4 antibody. Therefore, AIP may also affect extrapancreatic organs, and the sera of AIP patients may contain an IgG4 autoantibody to various organs.
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Affiliation(s)
- Hirotaka Ohara
- Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
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van Buuren HR, Vleggaar FP, Willemien Erkelens G, Zondervan PE, Lesterhuis W, Van Eijck CHJ, Puylaert JBCM, Van Der Werf SDJ. Autoimmune pancreatocholangitis: a series of ten patients. Scand J Gastroenterol 2007:70-8. [PMID: 16782625 DOI: 10.1080/00365520600664326] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
BACKGROUND During a 10-year period we observed 10 patients who suffered from an inflammatory-fibrosing disease mimicking pancreatic carcinoma and primary sclerosing cholangitis (PSC). METHODS A review of the presenting features, the clinical course and the relevant literature. RESULTS Ten male patients (mean age 55 years) presented with weight loss, jaundice and pruritus. Pancreatic cancer was suggested by imaging studies, which showed focal or generalized pancreatic enlargement and compression of the distal common bile duct. Cholangiography also demonstrated intrahepatic biliary stenoses consistent with sclerosing cholangitis. None had evidence of IBD. Exocrine pancreatic insufficiency was found in six cases and diabetes in four. Pancreatic histology (n=3) showed fibrosis and extensive inflammatory infiltrates. Immunosuppressive treatment was instituted in five patients. Clinical and biochemical remission occurred in three; in one other patient, previously documented intrahepatic biliary strictures had disappeared after 3 months. One patient had concomitant Sjögren's disease. The clinical features, pancreatic involvement, age at presentation, absence of IBD and response to steroids all plead against a diagnosis of "classical" PSC. The natural course of the disease was highly variable. Thirty-five comparable cases, with a largest series of three, have been reported in the literature. The disease has been associated with Sjögren's disease, retroperitoneal fibrosis and other fibrosing conditions, and may be a manifestation of a systemic fibro-inflammatory disorder. CONCLUSION Autoimmune pancreatocholangitis is a distinct inflammatory disorder involving the pancreas and biliary tree. The disease may mimick pancreatic carcinoma and PSC and responds to immunosuppressives.
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Affiliation(s)
- Henk R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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Smith T, Befeler AS. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Curr Gastroenterol Rep 2007; 9:54-9. [PMID: 17335678 DOI: 10.1007/s11894-008-0021-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that results in progressive fibrosis of intrahepatic and extrahepatic bile ducts. No effective therapy currently exists for this disease. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is the most promising treatment option because of its benign side effect profile and documented benefit in the treatment of other cholestatic liver diseases, including primary biliary cirrhosis. Multiple studies using standard-dosage (8-15 mg/kg/d) and high-dosage (20-30 mg/kg/d) UDCA generally show improvement in liver chemistries in PSC patients, and several show improvement in liver histology. However, the majority of trials using UDCA in PSC are underpowered and fail to show improvements in clinically relevant endpoints, such as delayed progression to cirrhosis, portal hypertension, liver transplantation, development of cholangiocarcinoma, or death.
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Affiliation(s)
- Timothy Smith
- Division of Gastroenterology and Hepatology, Saint Louis University, 3635 Vista at Grand Boulevard, St. Louis, MO 63110, USA.
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Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, Chari S, Lindor KD. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006; 101:2070-5. [PMID: 16879434 DOI: 10.1111/j.1572-0241.2006.00772.x] [Citation(s) in RCA: 231] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Biliary strictures, similar to primary sclerosing cholangitis (PSC), have been reported in patients with autoimmune pancreatitis, which is characterized by elevated serum IgG4 levels and responsiveness to corticosteroids. We sought to determine the frequency of elevated IgG4 in patients with PSC and to clinically compare PSC patients with elevated and normal IgG4 levels. METHODS We measured serum IgG4 in 127 patients with PSC and 87 patients with primary biliary cirrhosis, as disease controls. Demographic, clinical, and laboratory characteristics were compared between the PSC groups with normal and elevated IgG4 (>140 mg/dL). RESULTS Elevated IgG4 was found in 12 PSC patients (9%) versus one PBC patient (1.1%) (p= 0.017). Patients with elevated IgG4 had higher total bilirubin (p= 0.009), alkaline phosphatase (p= 0.01), and PSC Mayo risk score (p= 0.038), and lower frequency of IBD (p < 0.0001). Importantly, the time to liver transplantation was shorter in patients with elevated IgG4 (1.7 vs 6.5 yr, p= 0.0009). The type of biliary involvement (intrahepatic, extrahepatic, or both) and pancreatic involvement were similar in both groups. CONCLUSIONS A small proportion of PSC patients had elevated serum IgG4. In these patients parameters of liver disease severity were more pronounced and time to liver transplantation was shorter, suggesting a more severe disease course. It is possible that this subset of patients behaves similarly to autoimmune pancreatitis patients with biliary strictures, and could potentially respond to corticosteroids. Testing PSC patients for IgG4 and treating those with elevated levels with corticosteroids in clinical trials should be considered.
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Affiliation(s)
- Flavia D Mendes
- Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
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36
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Braun F, Behrend M. Basic immunosuppressive drugs outside solid organ transplantation. Expert Opin Investig Drugs 2006; 15:267-91. [PMID: 16503764 DOI: 10.1517/13543784.15.3.267] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immunosuppressive drugs are the backbone of solid organ transplantation. The introduction of new immunosuppressive drugs led to improved patient and organ survival rates. Nowadays, acute rejection can be reduced to a minimum. Individualization and avoidance of drug-related adverse effects became a new goal to achieve. The potency of immunosuppressive drugs makes them attractive for use in various autoimmune diseases; therefore, the experience on immunosuppressive drugs outside the field of organ transplantation is analysed in this review.
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Affiliation(s)
- Felix Braun
- General and Transplantation Surgery, University of Kiel, Germany
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37
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Danese S, Semeraro S, Papa A, Roberto I, Scaldaferri F, Fedeli G, Gasbarrini G, Gasbarrini A. Extraintestinal manifestations in inflammatory bowel disease. World J Gastroenterol 2006; 11:7227-36. [PMID: 16437620 PMCID: PMC4725142 DOI: 10.3748/wjg.v11.i46.7227] [Citation(s) in RCA: 225] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) can be really considered to be systemic diseases since they are often associated with extraintestinal manifestations, complications, and other autoimmune disorders. Indeed, physicians who care for patients with ulcerative colitis and Crohn's disease, the two major forms of IBD, face a new clinical challenge every day, worsened by the very frequent rate of extraintestinal complications. The goal of this review is to provide an overview and an update on the extraintestinal complications occurring in IBD. Indeed, this paper highlights how virtually almost every organ system can be involved, principally eyes, skin, joints, kidneys, liver and biliary tracts, and vasculature (or vascular system) are the most common sites of systemic IBD and their involvement is dependent on different mechanisms.
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Affiliation(s)
- Silvio Danese
- Department of Internal Medicine, Catholic University School of Medicine, L.go Vito 1, Rome 00168, Italy.
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38
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Charatcharoenwitthaya P, Lindor KD. Primary sclerosing cholangitis: diagnosis and management. Curr Gastroenterol Rep 2006; 8:75-82. [PMID: 16510038 DOI: 10.1007/s11894-006-0067-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by progressive inflammatory destruction of intrahepatic and extrahepatic bile ducts, and ultimately cirrhosis. PSC occurs primarily in patients with underlying ulcerative colitis and affects primarily young to middle-aged men. PSC is believed to be an autoimmune disease mediated by immune dysregulation in patients with genetic susceptibility. One possible mechanism for the development of PSC is the homing of memory lymphocytes to the biliary tract. Cholangiography is the gold standard for diagnosis of PSC. The typical radiologic findings include multifocal strictures and dilation involving the intrahepatic or extrahepatic biliary tract, or both. Although no medical therapy has proved beneficial, a variety of agents have been tested, some of which appear promising and deserve further study. High-dose ursodeoxycholic acid may have benefit in slowing disease progression; a multicenter placebo-controlled trial is ongoing. Liver transplantation is a good option for patients with advanced PSC, although the disease can recur after successful transplantation.
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Abstract
In 1950, Waldenström was the first to describe a chronic form of hepatitis in young women. Subsequently, the disease was found to be associated with other autoimmune syndromes and was later termed "lupoid hepatitis" because of the presence of antinuclear antibodies. In 1965, it became designated by Mackay et al. as "autoimmune hepatitis" at an international meeting, at which the general concept of autoimmunity was endorsed by the scientific community. In the early 1960s and 1970s, the value of immunosuppressive therapy with glucocorticoids and/or azathioprine was well documented in several studies. The original association of autoimmune hepatitis (AIH) and HLA alleles, which has remarkably stood the test of time, was published in 1972. In the 1970s and 1980s, several autoantibodies were identified in patients with autoimmune hepatitis directed against proteins of the endoplasmatic reticulum expressed in liver and kidney and against soluble liver antigens. Subsequently, the molecular targets of these antibodies were identified and more precisely characterized. In the last two decades many additional pieces of the AIH puzzle have been collected leading to the identification of additional antibodies and genes associated with AIH and to the emergence of new therapeutic agents. Meanwhile, the immunoserological and genetic heterogeneity of AIH is well established and it has become obvious that clinical manifestations, disease behavior, and treatment outcome may vary by racial groups, geographical regions and genetic predisposition. Currently, the International Autoimmune hepatitis group is endorsing multi-center collaborative studies to more precisely define the features at disease presentation and to define prognostic indices and appropriate treatment algorithms. Given the importance of serological testing, the IAHG is also working on guidelines and procedures for more reliable and standardized testing of autoantibodies.
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Affiliation(s)
- Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
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40
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Huang CS, Lichtenstein DR. Treatment of Biliary Problems in Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2005; 8:117-126. [PMID: 15769433 DOI: 10.1007/s11938-005-0004-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The most common biliary problem in patients with inflammatory bowel disease is primary sclerosing cholangitis (PSC). The treatment of this disease is multifaceted and frequently requires a multidisciplinary approach involving internists, nutritionists, gastroenterologists, and surgeons. Unfortunately, other than liver transplantation, no therapy that is currently available has been proven to alter the natural history of PSC or prolong survival. Ursodeoxycholic acid is currently the most promising pharmacologic treatment option for slowing disease progression and should be used in higher than usual doses (20 to 30 mg/kg/d). Treatment of symptoms due to cholestasis, such as pruritis and steatorrhea, is an important aspect of the medical care of patients with PSC. Our preferred treatment of pruritis due to cholestasis is with bile acid binding exchange resins such as cholestyramine or colestipol (which is generally better tolerated than cholestyramine). Endoscopic therapy should be reserved for patients with obstructive jaundice, cholangitis, or symptomatic dominant biliary strictures. We recommend dilation of dominant strictures with graduated or balloon dilators followed by temporary stenting if the postdilation cholangiographic appearance is not improved or adequate biliary drainage cannot be assured. There is indirect evidence that the combination of ursodeoxycholic acid and endoscopic therapy to maintain biliary patency may improve transplant-free survival in patients with PSC, although this remains to be proven. Liver transplantation remains the only effective treatment of advanced PSC, and should be considered in patients with complications of cirrhosis or intractable pruritis or fatigue.
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Affiliation(s)
- Christopher S Huang
- Boston University School of Medicine, Boston Medical Center, 85 East Concord Street, Boston, MA 02118, USA.
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41
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Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor KD. Mycophenolate mofetil for the treatment of primary sclerosing cholangitis. Am J Gastroenterol 2005; 100:308-12. [PMID: 15667487 DOI: 10.1111/j.1572-0241.2005.40484.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Despite advances in understanding the pathophysiology underlying this disorder, no effective medical therapy has been identified for halting disease progression. The aim of this investigation was to determine the safety and estimated efficacy of mycophenolate mofetil (MMF) for the treatment of PSC. Thirty patients with PSC received MMF 1 g daily to a maximum of 3 g daily for 1 yr. Liver tests were determined at 3-month intervals with the Mayo risk score calculated at baseline and at the end of therapy. Twenty-three (77%) patients completed 1 yr of therapy. Significant but clinically marginal improvement in serum alkaline phosphatase level after 1 yr of therapy was observed (1135 +/- 581 U/L vs 912 +/- 463 U/L, p= 0.02). No other significant changes in liver biochemistries or Mayo risk score was observed. Seven patients (23%) discontinued MMF due to adverse events possibly related to therapy. Adverse reactions resolved spontaneously or with dose reduction in 10 (33%) patients. One patient developed pancreatitis, bacterial cholangitis, and sepsis during the eighth month of MMF therapy. No patient developed cytopenia on therapy. In conclusion, MMF does not appear to have clinically important benefits for PSC despite being tolerated by most patients. The results of this pilot study do not support further study of MMF as a single agent in the treatment of PSC.
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Affiliation(s)
- Jayant A Talwalkar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 SW First Street, Rochester, MN 55905, USA
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42
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Färkkilä M, Karvonen AL, Nurmi H, Nuutinen H, Taavitsainen M, Pikkarainen P, Kärkkäinen P. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 2004; 40:1379-86. [PMID: 15565569 DOI: 10.1002/hep.20457] [Citation(s) in RCA: 155] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
No effective medical therapy is currently available for primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA) improves liver enzymes, but its effect on liver histology is controversial. Metronidazole (MTZ) prevents PSC-like liver damage in animal models and reduces intestinal permeability. We recruited 80 patients with PSC into a randomized placebo-controlled study to evaluate the effect of UDCA and MTZ (UDCA/MTZ) compared with UDCA/placebo on the progression of PSC. Patients (41 UDCA/placebo and 39 UDCA/MTZ) were followed every third month. Assessment of liver function test, histological stage and grade, and cholangiography (via ERCP) at baseline showed no differences between the groups. After 36 months, serum aminotransferases gamma-glutamyltransferase, and alkaline phosphatase (ALP) decreased markedly in both groups, serum ALP more significantly in the UDCA/MTZ group (-337 +/- 54 U/L, P < .05) compared with the UDCA/placebo group. The New Mayo Risk Score decreased markedly only in the UDCA/MTZ group (-0.50 +/- 0.13, P < .01). The number of patients with improvement of stage (P < .05) and grade (P < .05) was higher in the combination group. ERCP findings showed no progression or improvement in 77% and 68% of patients on UDCA/MTZ and UDCA/placebo, respectively. In conclusion, combining MTZ with UDCA in PSC improved serum ALP levels and New Mayo Risk Score, but no statistically significant effect on disease progression as assessed via liver histology or ERCP was seen. Long-term studies using a higher dose of UDCA combined with MTZ in larger patient populations are indicated.
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Affiliation(s)
- Martti Färkkilä
- Division of Gastroenterology, Department of Medicine, Helsinki University Central Hospital, Finland.
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43
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Abstract
Primary sclerosing cholangitis is a cholestatic liver disease strongly associated with IBD. Considerable advances in the understanding of its pathogenesis have been made. The idea of autoimmunity affecting genetically susceptible individuals is largely accepted; however, much remains to be explained about the origin of this disease. Despite active investigation of different therapeutic modalities with the goal of modifying disease progression, liver transplantation continues to be the only option to provide survival benefit in these patients.
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Affiliation(s)
- Flavia D Mendes
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA
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44
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Geier A, Gartung C, Dietrich CG, Wasmuth HE, Reinartz P, Matern S. Side effects of budesonide in liver cirrhosis due to chronic autoimmune hepatitis: influence of hepatic metabolism versus portosystemic shunts on a patient complicated with HCC. World J Gastroenterol 2003; 9:2681-5. [PMID: 14669312 PMCID: PMC4612031 DOI: 10.3748/wjg.v9.i12.2681] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the systemic availability of budesonide in a patient with Child A cirrhosis due to autoimmune hepatitis (AIH) and primary hepatocellular carcinoma, who developed serious side effects.
METHODS: Serum levels of budesonide, 6β-OH-budesonide and 16α-OH-prednisolon were measured by HPLC/MS/MS; portosystemic shunt-index (SI) was determined by 99mTc nuclear imaging. All values were compared with a matched control patient without side effects.
RESULTS: Serum levels of budesonide were 13-fold increased in the index patient. The ratio between serum levels of the metabolites 6β-OH-budesonide and 16α-OH-prednisolone, respectively, and serum levels of budesonide was diminished (1.0 vs. 4.0 for 6β-OH-budesonide, 4.2 vs. 10.7 for 16α-OH-prednisolone). Both patients had portosystemic SI (5.7% and 3.1%) within the range of healthy subjects.
CONCLUSION: Serum levels of budesonide vary up to 13-fold in AIH patients with Child A cirrhosis in the absence of relevant portosystemic shunting. Reduced hepatic metabolism, as indicated by reduced metabolite-to-drug ratio, rather than portosystemic shunting may explain systemic side effects of this drug in cirrhosis.
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Affiliation(s)
- Andreas Geier
- Department of Internal Medicine III, University of Technology Aachen, Aachen, Germany.
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45
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Abstract
Infectious hepatitis is often the initial suspect when abnormal serum liver function test results are discovered in primary care settings. However, noninfectious liver disorders may also present with altered liver function tests. Noninfectious liver disorders require careful assessment of patient history, physical findings, and serum laboratory tests to distinguish among entities that have varying clinical implications and treatments.
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46
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Affiliation(s)
- Cynthia Levy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Mayo Building W 19 A, 200 1st street SW, Rochester, MN 55905, USA
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47
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Strassburg CP, Manns MP. Transition of care between paediatric and adult gastroenterology. Autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2003; 17:291-306. [PMID: 12676120 DOI: 10.1016/s1521-6918(03)00015-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare chronic disease of the liver with an excellent prognosis under medical therapy capable of reaching complete remission. The diagnosis of AIH relies on the exclusion of viral, metabolic, genetic and toxic aetiologies of chronic hepatitis, or hepatic injury. Autoantibodies contribute to the diagnosis of AIH and have led to the serological subclassification into three distinct types. Also, immunogenetic associations suggest heterogeneity of the syndrome of AIH. Treatment is not based on serological types but is uniformly employed for all subtypes of AIH. Although 90% of patients respond to treatment, immunosuppressive drugs used in transplant medicine have been employed for patients with treatment failure. New drugs, such as budenoside, are being evaluated for the long-term treatment of AIH with a reduction in steroid side-effects. Liver transplantation is an established treatment option for patients who fail to reach remission and progress to cirrhosis and liver failure. In Europe, about 4% of cirrhotic patients with the diagnosis of AIH undergo transplantation. The diagnosis and awareness of the disease is designed to reduce mortality and morbidity.
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Affiliation(s)
- Christian P Strassburg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany
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48
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic hepatobiliary disease that usually progresses to biliary cirrhosis and liver failure; it also predisposes to cholangiocarcinoma. The cause of PSC is unknown, although evidence suggests that the tissue damage is mediated by the immune system. There is an unexplained close association between PSC and inflammatory bowel disease, particularly in ulcerative colitis, which coexists in the majority of patients with PSC. No medical therapy has been proven to halt or reverse disease progression; however, recent preliminary evidence suggests that ursodeoxycholic acid (UDCA) in a high dose of 20 to 25 mg/kg may slow the disease process. Evidence from a pilot study suggests that the combination of UDCA and immunosuppressive therapy, such as prednisolone or azathioprine, may also increase efficacy. For patients with end-stage PSC, liver transplantation remains the only effective therapy, although there is clear evidence that PSC may recur in the liver allograft.
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Affiliation(s)
- Roger W Chapman
- Department of Hepatology and Gastroenterology, Oxford Radcliffe Hospital, Oxford OX3 9DU, UK.
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49
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Abstract
Autoimmune hepatitis is a well-established chronic liver disease. It primarily affects women, is characterized by circulating autoantibodies and elevated gammaglobulins and is associated with extrahepatic immune-mediated syndromes. Treatment regimens have remained unchanged for a number of years because of the high efficacy of steroid monotherapy, or combination therapy of azathioprine and steroids. In approximately 90% of patients remission of the disease is reached by medical therapy, which is usually administered lifelong because long-term remission after drug withdrawal is achieved in only 17% of patients. In 10% of patients treatment failure is observed. The challenge of remission induction involves the use of transplant immunosuppressants such as cyclosporine, mycophenolate moffetil, and tacrolimus. The challenge of maintenance therapy minimizing steroid side-effects involves the evaluation of topical steroids and the use of azathioprine monotherapy. Overlap syndromes occur in approximately 20% of autoimmune liver diseases. The diagnosis is broadly based on serological, biochemical, clinical and histological parameters. Most common are the overlap of autoimmune hepatitis and primary biliary cirrhosis, as well as autoimmune hepatitis with primary sclerosing cholangitis. These yet incompletely defined syndromes are an important differential diagnosis in the difficult-to-treat patient with autoimmune hepatitis.
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Affiliation(s)
- Arndt Vogel
- Department of Hepatology, Gastroenterology and Endocrinology, Hannover Medical School, Hannover, Germany
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50
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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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