|
1
|
Reovirus uses temporospatial compartmentalization to orchestrate core versus outercapsid assembly. PLoS Pathog 2022; 18:e1010641. [PMID: 36099325 PMCID: PMC9514668 DOI: 10.1371/journal.ppat.1010641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/27/2022] [Accepted: 08/25/2022] [Indexed: 11/19/2022] Open
Abstract
Reoviridae virus family members, such as mammalian orthoreovirus (reovirus), encounter a unique challenge during replication. To hide the dsRNA from host recognition, the genome remains encapsidated in transcriptionally active proteinaceous core capsids that transcribe and release +RNA. De novo +RNAs and core proteins must repeatedly assemble into new progeny cores in order to logarithmically amplify replication. Reoviruses also produce outercapsid (OC) proteins μ1, σ3 and σ1 that assemble onto cores to create highly stable infectious full virions. Current models of reovirus replication position amplification of transcriptionally-active cores and assembly of infectious virions in shared factories, but we hypothesized that since assembly of OC proteins would halt core amplification, OC assembly is somehow regulated. Kinetic analysis of virus +RNA production, core versus OC protein expression, and core particles versus whole virus particle accumulation, indicated that assembly of OC proteins onto core particles was temporally delayed. All viral RNAs and proteins were made simultaneously, eliminating the possibility that delayed OC RNAs or proteins account for delayed OC assembly. High resolution fluorescence and electron microscopy revealed that core amplification occurred early during infection at peripheral core-only factories, while all OC proteins associated with lipid droplets (LDs) that coalesced near the nucleus in a μ1–dependent manner. Core-only factories transitioned towards the nucleus despite cycloheximide-mediated halting of new protein expression, while new core-only factories developed in the periphery. As infection progressed, OC assembly occurred at LD-and nuclear-proximal factories. Silencing of OC μ1 expression with siRNAs led to large factories that remained further from the nucleus, implicating μ1 in the transition to perinuclear factories. Moreover, late during infection, +RNA pools largely contributed to the production of de-novo viral proteins and fully-assembled infectious viruses. Altogether the results suggest an advanced model of reovirus replication with spatiotemporal segregation of core amplification, OC complexes and fully assembled virions. It is important to understand how viruses replicate and assemble to discover antiviral therapies and to modify viruses for applications like gene therapy or cancer therapy. Reovirus is a harmless virus being tested as a cancer therapy. Reovirus has two coats of proteins, an inner coat and an outer coat. To replicate, reovirus particles need only the inner coat, but to become infectious they require the outer coat. Strangely, inner and outer coat proteins are all made by the virus at once, so it was unknown what determines whether newly made viruses will contain just the inner coat to continue to replicate, or both coats to transmit to new hosts. Our experiments reveal that the inner coat proteins are located in a different area of an infected cell versus the outer coat proteins. The location therefore determines if the newly made viruses contain just the inner coat versus both coats. Reoviruses have evolved extravagant mechanisms to be able to efficiently take on the best composition required for replication and transmission.
Collapse
|
|
2
|
Minuk GY, Pollock G, Uhanova J. Adult idiopathic cholestasis: a condition more common in the Canadian Inuit? Int J Circumpolar Health 2017; 76:1388104. [PMID: 29034810 PMCID: PMC5645770 DOI: 10.1080/22423982.2017.1388104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Despite extensive investigations, some patients have no identifiable cause for their cholestatic liver enzyme abnormalities. The aim of this study was to document the clinical, laboratory, radiologic and histologic features of adult patients with idiopathic cholestasis (AIC). A computerised database of referred patients to a tertiary care hospital outpatient department for assessment of hepatobiliary disorders between 2005 and 2015 was employed to identify and describe features associated with AIC. Of 6,560 patient referrals, sufficient documentation to warrant a diagnosis of AIC was present in 17 (0.26%) cases. Of the 17, a disproportionate number were Canadian Inuit (7/60, 12% Inuit referrals vs. 10/6,500, 0.16% non-Inuit referrals, p<0.0001). The median age of the 17 subjects was 57 years and nine (53%) were female. Clinical and/or laboratory evidence of autoimmune disorders was present in six (35%) cases. Clinical features of hepatic decompensation, radiologic findings in keeping with cirrhosis and histologic confirmation of cirrhosis were present in 47%, 31% and 42% of individuals, respectively. There were no significant improvements in cholestatic liver enzymes and function tests in those treated with ursodiol and/or immunomodulants (n=7) compared to those left untreated (n=10). In conclusion, AIC is a rare condition diagnosed by exclusion. It appears to be more common in the Canadian Inuit population and those with autoimmune disorders. Advanced liver disease is a frequent finding at presentation. Intervention with ursodiol and/or immunomodulants does not appear to be of therapeutic value.
Collapse
Affiliation(s)
- Gerald Y Minuk
- a Section of Hepatology, Department of Medicine , College of Medicine, University of Manitoba , Winnipeg , Canada.,b Department of Pharmacology and Therapeutics , College of Medicine, University of Manitoba , Winnipeg , Canada
| | - Galia Pollock
- a Section of Hepatology, Department of Medicine , College of Medicine, University of Manitoba , Winnipeg , Canada
| | - Julia Uhanova
- a Section of Hepatology, Department of Medicine , College of Medicine, University of Manitoba , Winnipeg , Canada
| |
Collapse
|
|
3
|
Abstract
Naturally occurring reoviruses are live replication-proficient viruses that specifically infect human cancer cells while sparing their normal counterpart. Since the discovery of reoviruses in 1950s, they have shown various degrees of safety and efficacy in pre-clinical or clinical applications for human anti-cancer therapeutics. I have recently discovered that cellular tumor suppressor genes are also important in determining reoviral tropism. Carcinogenesis is a multi-step process involving the accumulation of both oncogene and tumor suppressor gene abnormalities. Reoviruses can exploit abnormal cellular tumor suppressor signaling for their oncolytic specificity and efficacy. Many tumor suppressor genes such as p53, ataxia telangiectasia mutated (ATM), and retinoblastoma associated (RB) are known to play important roles in genomic fidelity/maintenance. Thus, a tumor suppressor gene abnormality could affect host genomic integrity and likely disrupt intact antiviral networks due to the accumulation of genetic defects which in turn could result in oncolytic reovirus susceptibility. This review outlines the discovery of oncolytic reovirus strains, recent progresses in elucidating the molecular connection between oncogene/tumor suppressor gene abnormalities and reoviral oncotropism, and their clinical implications. Future directions in the utility of reovirus virotherapy is also proposed in this review.
Collapse
Affiliation(s)
- Manbok Kim
- Department of Medical Science, Dankook University College of Medicine, Cheonan 31116, Korea
| |
Collapse
|
|
4
|
Abstract
Oncolytic viruses represent a new class of therapeutic agents that promote anti-tumour responses through a dual mechanism of action that is dependent on selective tumour cell killing and the induction of systemic anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been developed as oncolytic agents, and the approval of the first oncolytic virus by the US Food and Drug Administration (FDA) is anticipated in the near future. This Review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describes oncolytic viruses in advanced clinical trials and discusses the unique challenges in the development of oncolytic viruses as a new class of drugs for the treatment of cancer.
Collapse
Affiliation(s)
- Howard L. Kaufman
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, Room 2004, New Brunswick, 08901 New Jersey USA
| | - Frederick J. Kohlhapp
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, Room 2004, New Brunswick, 08901 New Jersey USA
| | - Andrew Zloza
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, Room 2004, New Brunswick, 08901 New Jersey USA
| |
Collapse
|
|
5
|
Kolb EA, Sampson V, Stabley D, Walter A, Sol-Church K, Cripe T, Hingorani P, Ahern CH, Weigel BJ, Zwiebel J, Blaney SM. A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: a Children's Oncology Group Phase I Consortium report. Pediatr Blood Cancer 2015; 62:751-8. [PMID: 25728527 PMCID: PMC4376570 DOI: 10.1002/pbc.25464] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 01/19/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Reovirus is a naturally occurring human virus that is cytopathic to malignant cells possessing an activated Ras signaling pathway. We conducted a phase I trial of Reolysin, a manufactured, proprietary isolate of purified reovirus, in children with relapsed/refractory extracranial solid tumors to define the recommended phase 2 dose (RP2D), toxicities, and pharmacokinetic properties when administered as a single agent or in combination with cyclophosphamide. PROCEDURES Reolysin was administered intravenously for 5 consecutive days, every 28 days. Using a 3 + 3 design, the following dose levels were evaluated: 3 × 10(8) Tissue Culture Inhibitory Dose 50% (TCID50 )/kg; 5 × 10(8) TCID50 /kg (maximum dose was 3 × 10(10) TCID50 ); and 5 × 10(8) TCID50 /kg plus oral cyclophosphamide (50 mg/m(2) /day × 21 days). RESULTS Twenty-nine patients were enrolled; 28 were eligible and 24 were evaluable for toxicity and response. There were no hematologic dose-limiting toxicities. Grade 5 respiratory failure and a Grade 5 thromboembolic event were reported, both in the setting of progressive disease. The median time to clear the reovirus viremia was 6.5 days. Eight of 24 patients were viremic beyond the 5 days of therapy, all were negative by day 17. No patient had detectable viral RNA in saliva or stool. There were no objective responses. CONCLUSIONS Reolysin at a dose of 5 × 10(8) TCID50 /kg daily for 5 days was well tolerated in children alone and in combination with oral cyclophosphamide. Virus was cleared rapidly from the serum and shedding in stool and saliva was not detectable.
Collapse
Affiliation(s)
- E. Anders Kolb
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, DE
| | - Valerie Sampson
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, DE
| | - Deborah Stabley
- Nemours Biomolecular Core Laboratory, Nemours/A.I. duPont Hospital for Children, Wilmington, DE
| | - Alexa Walter
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, DE
| | - Katia Sol-Church
- Nemours Biomolecular Core Laboratory, Nemours/A.I. duPont Hospital for Children, Wilmington, DE
| | - Timothy Cripe
- Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, The Ohio State University, Columbus, OH
| | - Pooja Hingorani
- Division of Hematology and Oncology, Phoenix Children's Hospital, Phoenix, AZ
| | - Charlotte Hsieh Ahern
- Department of Medicine, Division of Biostatistics, Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX
| | - Brenda J. Weigel
- Division of Hematology and Oncology, University of Minnesota, Amplatz Children's Hospital, Minneapolis, MN
| | - James Zwiebel
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD
| | - Susan M. Blaney
- Department of Medicine, Hematology-Oncology, Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX
| |
Collapse
|
|
6
|
Abstract
Metastatic colorectal cancer is a prevalent disease for which novel targeted therapies and biologically based combinations are under development. Cytotoxic chemotherapy doublets (FOLFOX, FOLFIRI) and triplets (FOLFOXIRI) in combination with biologics are standard regimens, and efforts are ongoing to delineate the optimal sequence for each patient based on unique underlying tumor biology. Molecular profiling of metastatic colorectal cancer (including mutational analysis for KRAS, NRAS, BRAF, PIK3CA, and others) has become increasingly important for identification of prognostic and predictive biomarkers, as well as for insights into the biology that drives the tumor. Large comprehensive analyses such as that of The Cancer Genome Atlas have provided important clues into carcinogenesis and discerned potentially druggable targets for metastatic colorectal cancer. Novel therapeutic agents currently under investigation for subtypes of this disease include immunotherapies such as anti–programmed cell death receptor antibody, cancer stem cell inhibitors, targeted combinations such as BRAF and PI3K inhibitors, and the anti-RAS reovirus Reolysin®.
Collapse
Affiliation(s)
- Kristen K. Ciombor
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210;, ,
| | - Christina Wu
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210;, ,
| | - Richard M. Goldberg
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210;, ,
| |
Collapse
|
|
7
|
Landi A, Weismuller TJ, Lankisch TO, Santer DM, Tyrrell DLJ, Manns MP, Houghton M. Differential serum levels of eosinophilic eotaxins in primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis. J Interferon Cytokine Res 2013; 34:204-14. [PMID: 24168449 DOI: 10.1089/jir.2013.0075] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
To investigate pathogenic mechanisms of primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and autoimmune hepatitis (AIH), serum levels of 26 chemokines and cytokines were determined and compared with patients with chronic hepatitis C or in healthy controls. The chemokine eotaxin-3 (E3; CCL26), which recruits eosinophils to sites of inflammation, was found to be highly elevated in all PSC, PBC, and AIH patients compared with HCV patients and healthy controls. Eotaxin-1 (E1; CCL11), another eosinophil-specific chemokine, was elevated in PSC but reduced in PBC and AIH, while the macrophage-derived chemokine (MDC; CCL22) was lower in all PSC, PBC, and AIH patients compared with HCV patients and controls. By incorporating levels of the interleukin (IL)-15 into a diagnostic algorithm, PSC, PBC, and AIH patients could each be differentiated with good sensitivity and specificity. These findings represent the first study to compare the level of serum cytokine/chemokine levels among these related autoimmune-like liver diseases. Furthermore, our data indicate that the measurement of serum E3, E1, CCL22, and IL-15 levels can aid in the diagnosis of these clinically challenging diseases and shed light on the potential pathogenic mechanisms underlying these diseases. By suggesting a potential role for an allergic phenomenon involving eosinophils, which may define them as liver-specific allergic diseases, this may open up potential new therapeutic avenues by abrogating the action of these disease-associated immune modulators.
Collapse
Affiliation(s)
- Abdolamir Landi
- 1 Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta , Edmonton, Canada
| | | | | | | | | | | | | |
Collapse
|
|
8
|
Galanis E, Markovic SN, Suman VJ, Nuovo GJ, Vile RG, Kottke TJ, Nevala WK, Thompson MA, Lewis JE, Rumilla KM, Roulstone V, Harrington K, Linette GP, Maples WJ, Coffey M, Zwiebel J, Kendra K. Phase II trial of intravenous administration of Reolysin(®) (Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma. Mol Ther 2012; 20:1998-2003. [PMID: 22871663 PMCID: PMC3464629 DOI: 10.1038/mt.2012.146] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 06/27/2012] [Indexed: 02/07/2023] Open
Abstract
Reovirus, a replication competent RNA virus, has preclinical activity against melanoma lines and xenografts. We conducted a phase II trial of reovirus in metastatic melanoma patients. Patients received 3 × 10(10) TCID50 on days 1-5 of each 28 day cycle, administered intravenously. Twenty-one eligible patients were enrolled. Treatment was well tolerated without any dose reductions having to be implemented. Post-treatment biopsy samples were obtained in 15 patients, 13/15 contained adequate tumor for correlative analysis. In two patients, productive reoviral replication (viral antigen coexpression with tubulin) was demonstrated, despite increase in neutralizing antibody titers. There were no objective responses although 75-90% tumor necrosis, consistent with treatment effect, was observed in one patient who had metastatic lesions surgically removed. Median time to progression and survival were 45 days (range 13-96 days) and 165 days (range 15 days-15.8 months) respectively. In conclusion, reovirus treatment was well tolerated in metastatic melanoma patients; viral replication was demonstrated in biopsy samples. Based on preclinical data showing synergy with taxane and platinum compounds, a phase II combination trial in metastatic melanoma patients is ongoing.
Collapse
|
|
9
|
Fosby B, Karlsen TH, Melum E. Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. World J Gastroenterol 2012; 18:1-15. [PMID: 22228965 PMCID: PMC3251800 DOI: 10.3748/wjg.v18.i1.1] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease affecting the bile ducts, leading to fibrosis and eventually cirrhosis in most patients. Its etiology is unknown and so far no effective medical therapy is available. Liver transplantation (LTX) is the only curative treatment and at present PSC is the main indication for LTX in the Scandinavian countries. Close to half of the PSC patients experience one or more episodes of acute cellular rejection (ACR) following transplantation and approximately 1/5 of the transplanted patients develop recurrent disease in the graft. In addition, some reports indicate that ACR early after LTX for PSC can influence the risk for recurrent disease. For these important post-transplantation entities affecting PSC patients, we have reviewed the current literature on epidemiology, pathogenesis, treatment and the possible influence of rejection on the risk of recurrent disease in the allograft.
Collapse
|
|
10
|
Hammill AM, Conner J, Cripe TP. Oncolytic virotherapy reaches adolescence. Pediatr Blood Cancer 2010; 55:1253-63. [PMID: 20734404 DOI: 10.1002/pbc.22724] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Accepted: 06/01/2010] [Indexed: 01/11/2023]
Abstract
Lytic viruses kill cells as a consequence of their normal replication life cycle. The idea of harnessing viruses to kill cancer cells arose over a century ago, before viruses were even discovered, from medical case reports of infections associated with cancer remissions. Since then, there has been no shortage of hype, hope, or fear regarding the prospect of oncolytic virotherapy for cancer. Early developments in the field included encouraging antitumor efficacy both in animal studies in the 1920s-1940s and in human clinical trials in the 1950s-1970s. Despite its long-standing history, oncolytic virotherapy was an idea ahead of its time. Without needed advances in molecular biology, virology, immunology, and clinical research ethics, early clinical trials resulted in infectious complications and were fraught with controversial research conduct, so that enthusiasm in the medical community waned. Oncolytic virotherapy is now experiencing a major growth spurt, having sustained numerous laboratory advances and undergone multiple encouraging adult clinical trials, and is now witnessing the emergence of pediatric trials. Here we review the history and salient biology of the field, including preclinical and clinical data, with a special emphasis on those agents now being tested in pediatric cancer patients.
Collapse
Affiliation(s)
- Adrienne M Hammill
- Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | | | | |
Collapse
|
|
11
|
Knight C, Murray KF. Hepatobiliary associations with inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2009; 3:681-91. [PMID: 19929587 DOI: 10.1586/egh.09.53] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatobiliary disease is not uncommon in patients with inflammatory bowel disease (IBD). The most common autoimmune hepatic associations are primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). The immunosuppressant medications used in the treatment of IBD also have potential hepatotoxicity. PSC is most commonly associated with IBD, specifically ulcerative colitis. AIH, a more classic autoimmune disease diagnosed commonly in isolation of other conditions in the same individual, is less commonly associated with IBD. Additionally, a subgroup of patients have features of both PSC and AIH, termed overlap syndrome, that is also sometimes seen in IBD patients. This review will discuss the most common liver disease associations seen in patients with IBD: PSC, AIH and overlap syndrome. Additionally, the most common drug-related hepatotoxicities encountered when treating IBD will be reviewed.
Collapse
Affiliation(s)
- Crystal Knight
- Seattle Children's and University of Washington School of Medicine, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, 4800 Sand Point Way, NE, PO Box 5371/W-7830, Seattle, WA 98105, USA.
| | | |
Collapse
|
|
12
|
Stanca CM, Babar J, Singal V, Ozdenerol E, Odin JA. Pathogenic role of environmental toxins in immune-mediated liver diseases. J Immunotoxicol 2009; 5:59-68. [PMID: 18382859 DOI: 10.1080/15476910802019086] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Immune-mediated liver diseases contribute significantly to morbidity and mortality due to liver failure and the need for liver transplantation. The pathogenesis of the immune-mediated chronic liver diseases, primary sclerosing cholangitis, autoimmune hepatitis, and primary biliary cirrhosis, is poorly understood. Genetic susceptibility factors may play a role, but increasing attention is being given to the association between environmental factors and these diseases. The existence of such a relationship is supported by epidemiologic surveys, animal models, and geographic clustering analyses. Unearthing the cause of this association may provide insight into the pathogenesis of immune-mediated chronic liver diseases and autoimmunity.
Collapse
Affiliation(s)
- Carmen M Stanca
- Department of Medicine, The Mount Sinai School of Medicine, New York, New York 10029, USA
| | | | | | | | | |
Collapse
|
|
13
|
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.
Collapse
|
|
14
|
Barton ES, Youree BE, Ebert DH, Forrest JC, Connolly JL, Valyi-Nagy T, Washington K, Wetzel JD, Dermody TS. Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease. J Clin Invest 2003; 111:1823-33. [PMID: 12813018 PMCID: PMC161418 DOI: 10.1172/jci16303] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Infection of neonatal mice with some reovirus strains produces a disease similar to infantile biliary atresia, but previous attempts to correlate reovirus infection with this disease have yielded conflicting results. We used isogenic reovirus strains T3SA- and T3SA+, which differ solely in the capacity to bind sialic acid as a coreceptor, to define the role of sialic acid in reovirus encephalitis and biliary tract infection in mice. Growth in the intestine was equivalent for both strains following peroral inoculation. However, T3SA+ spread more rapidly from the intestine to distant sites and replicated to higher titers in spleen, liver, and brain. Strikingly, mice infected with T3SA+ but not T3SA- developed steatorrhea and bilirubinemia. Liver tissue from mice infected with T3SA+ demonstrated intense inflammation focused at intrahepatic bile ducts, pathology analogous to that found in biliary atresia in humans, and high levels of T3SA+ antigen in bile duct epithelial cells. T3SA+ bound 100-fold more efficiently than T3SA- to human cholangiocarcinoma cells. These observations suggest that the carbohydrate-binding specificity of a virus can dramatically alter disease in the host and highlight the need for epidemiologic studies focusing on infection by sialic acid-binding reovirus strains as a possible contributor to the pathogenesis of neonatal biliary atresia.
Collapse
Affiliation(s)
- Erik S Barton
- Department of Microbiology and Immunology and Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Ponsioen CY, Defoer J, Ten Kate FJW, Weverling GJ, Tytgat GNJ, Pannekoek Y, Wertheim-Dillen PME. A survey of infectious agents as risk factors for primary sclerosing cholangitis: are Chlamydia species involved? Eur J Gastroenterol Hepatol 2002; 14:641-8. [PMID: 12072598 DOI: 10.1097/00042737-200206000-00009] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The aetiology of primary sclerosing cholangitis (PSC) is unknown, and the role of micro-organisms has been studied only to a limited extent. We tested the hypothesis that past or persisting infection with common viruses or atypical bacteria might play a role in genetically susceptible hosts. DESIGN Case-control study. METHODS Serological screening for antibodies against 22 viruses as well as Chlamydia spp. and Mycoplasma pneumoniae was carried out in 41 well-established PSC patients. All 5110 sera tested in 1997 for these micro-organisms at our laboratory served as a background reference group. Subsequently, Chlamydia anti-lipopolysaccharide (LPS) antibodies were determined by enzyme-linked immunosorbent assay (ELISA) in the PSC group and in three race-matched control groups (inflammatory bowel disease (IBD) group, n = 35; non-IBD patients group, n = 39; healthy blood donor group, n = 40). Subtyping in Chlamydia trachomatis and C. pneumoniae serotypes by specific anti-major outer membrane protein (MOMP) assays was carried out in the four groups. Immunohistochemical staining using specific markers for chlamydiae was carried out on liver biopsies of 14 PSC patients. RESULTS There was a markedly elevated seroprevalence of Chlamydia-LPS antibodies compared with the 1997 reference group. The odds ratios (ORs) for the presence of immunoglobulin G, immunoglobulin M and immunoglobulin A antibodies for the PSC patients versus the control group were 2.4 (95% confidence interval (CI) 1.1 to 5.4), 1.9 (95% CI 0.9 to 4.0) and 6.7 (95% CI 3.0 to 17.0), respectively. All other micro-organisms tested showed normal antibody profiles that did not differ from the 1997 reference group. The seroprevalence of Chlamydia-anti-LPS antibodies was elevated markedly in the PSC patients compared with the IBD, non-IBD and blood donor groups. The outcomes in the C. trachomatis and C. pneumoniae anti-MOMP assays did not correlate with the anti-LPS-positive PSC sera. The actual presence of Chlamydia bodies in liver tissue could not be demonstrated. CONCLUSION Our findings suggest an association between PSC and (previous) infection with Chlamydia.
Collapse
Affiliation(s)
- Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
| | | | | | | | | | | | | |
Collapse
|
|
16
|
Abstract
Several distinct conditions are characterized by a reduction in the number of small and medium-sized intrahepatic bile ducts. These diseases are associated with progressive cholestasis, which in turn leads to biliary fibrosis and ultimately cirrhosis. The best-characterized ductopenic condition in adulthood is primary biliary cirrhosis (PBC) for which there is now strong evidence of an autoimmune cause. The antigenic targets are epitopes on proteins of the 2-oxoacid dehydrogenase complex within mitochondria. Some of these proteins appear to be aberrantly expressed at the surface of cholangiocytes in PBC. The basis for the breakdown in tolerance remains uncertain, although there is recent evidence to indicate that apoptosis may play a key role at early stages in the pathogenesis of the disease. Related conditions include autoimmune overlap syndromes and AMA-negative PBC (autoimmune cholangitis). Primary sclerosing cholangitis is clinically and histologically distinct, although there is evidence that it also may have an immune-mediated cause. Ductopenia may also arise on the basis of drug-induced injury; the best example of this is progressive cholestasis complicating chlorpromazine therapy.
Collapse
Affiliation(s)
- Alastair D Burt
- Centre for Liver Research, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 4LP, UK.
| |
Collapse
|
|
17
|
Abstract
Many hepatobiliary diseases are seen in IBD. PSC is the most common, occurring in 7.5% of patients with UC. The cause of PSC is not well understood, but PSC seems to be associated with genetic susceptibility, sharing some immunologic abnormalities with UC. A characteristic cholangiogram in a patient with abnormal liver function tests usually establishes the diagnosis. Liver biopsy is not essential but can help make the diagnosis of small duct PSC in patients with a normal cholangiogram. There are no medications that treat PSC effectively. Endoscopic dilation of dominant strictures reduces the frequency of cholangitis and may improve survival. OLT remains the only proven treatment of advanced PSC. Cholangiocarcinoma is a feared complication of PSC that is difficult to diagnose. Cholelithiasis, PBC, portal vein thrombosis, and hepatic abscess are hepatobiliary disorders that occur less frequently in IBD patients.
Collapse
Affiliation(s)
- Jawad Ahmad
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC-Presbyterian, M-2, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | | |
Collapse
|
|
18
|
Affiliation(s)
- K L Norman
- Cancer Biology Research Group and Department of Microbiology and Infectious Diseases, University of Calgary, Room B855, Health Sciences Building, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1
| | | | | |
Collapse
|
|
19
|
Abstract
Primary biliary cirrhosis and primary sclerosing cholangitis are well recognized chronic cholestatic liver diseases that are considered to have an autoimmune basis. Recent progress in the study of autoimmune liver diseases has improved the recognition and characterization of these conditions. An important component of this progress has been the identification of liver disease-associated autoantibodies and their respective target antigens, and the development of specific assays for these autoantibodies. In addition, some nonhumoral immunological findings imply an involvement of specific immunopathogenic mechanisms in the development of these conditions. Furthermore, immunogenetic factors associated with increased susceptibility to some of these diseases have been identified. This article reviews the most relevant information relating to the postulated autoimmune pathogenesis of these diseases, with special emphasis on their associated humoral and cellular immunological abnormalities and immunopathogenetic factors. Some of the remaining important unresolved issues relating to the pathogenesis of these diseases, that need to be addressed in further research, are highlighted.
Collapse
Affiliation(s)
- J Medina
- Novartis Pharma AG, Basel, Switzerland
| | | | | | | |
Collapse
|
|
20
|
Affiliation(s)
- K L Norman
- Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Canada
| | | |
Collapse
|
|
21
|
Abstract
PSC is the most common of the clinically significant hepatobiliary diseases seen in association with IBD, with an incidence that varies from 2.5% to 7.5%. Conversely, 50% to 75% of patients with PSC have IBD. This high degree of association suggests a common pathogenetic mechanism; however, no causal relationship has been established. The etiopathogenesis of PSC remains poorly understood, despite a large number of studies looking at differing hypotheses. The diagnosis is usually established by cholangiography. Liver biopsy can sometimes be helpful in diagnosing pericholangitis. There is a significant overlap of the histology with chronic hepatitis. Serum markers have been studied for diagnosing PSC, particularly for early diagnosis of cholangiocarcinoma, but none have shown the high sensitivity and specificity needed to use them clinically. PSC usually progresses insidiously and eventually leads to cirrhosis. Despite progress in early recognition, optimal management of patients with PSC remains a challenge requiring a multidisciplinary approach among hepatologists, endoscopists, surgeons, and interventional radiologists. Colectomy for ulcerative colitis does not alter the natural history of PSC. There is a high (10% to 15%) incidence of cholangiocarcinoma in patients with PSC. This incidence along with the risk of colon cancer in patients with ulcerative colitis makes it necessary to follow these patients closely. A number of pharmacologic therapies have been evaluated, but none has proven successful in slowing the progression of PSC or prolonging survival. Endoscopic therapy has a proven utility in treating complications of recurrent cholangitis or worsening jaundice in the setting of a dominant stricture, but endoscopy has not been shown to improve survival or decrease the need for liver transplantation. Liver transplantation is life-saving for patients with advanced PSC. Pericholangitis, gallstones, and chronic hepatitis are additional disorders noted in association with IBD, but they are much less common and easier to manage than PSC.
Collapse
Affiliation(s)
- V Raj
- Department of Internal Medicine, University of Arkansas for Medical Sciences College of Medicine, McClellan VA Hospital (VR), Little Rock, USA
| | | |
Collapse
|
|
22
|
Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM, Narkewicz MR, Tyson RW, Murphy JR, Low R, Brown WR. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 1998; 27:1475-82. [PMID: 9620316 DOI: 10.1002/hep.510270603] [Citation(s) in RCA: 157] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Extrahepatic biliary atresia (EHBA) and choledochal cysts (CDC) are important causes of obstructive jaundice in pediatric patients. Viruses in general, and reoviruses in particular, have long been considered as possible etiologic agents responsible for inciting the inflammatory process that leads to these infantile obstructive cholangiopathies. In an effort to determine whether reovirus infection is associated with these disorders, we used a sensitive and specific reverse-transcriptase polymerase chain reaction (RT-PCR) technique designed to amplify a portion of the reovirus L1 gene segment from extracts of liver and/or biliary tissues. These tissues were obtained at the time of liver biopsy or surgical procedures from 23 patients with EHBA, 9 patients with CDC, and 33 patients with other hepatobiliary diseases. Hepatic and biliary tissues obtained at autopsy from 17 patients who died without known liver or biliary disease were also analyzed. Reovirus RNA was detected in hepatic and/or biliary tissues from 55% of patients with EHBA and 78% of patients with CDC. Reovirus RNA was found also in extracts of hepatic and/or biliary tissue from 21% of patients with other hepatobiliary diseases and in 12% of autopsy cases. The prevalence of reovirus RNA in tissues from patients with EHBA and CDC was significantly greater than that in patients with other hepatobiliary diseases (chi2 P = .012 EHBA vs. OTHER, P = .001 CDC vs. OTHER), or AUTOPSY cases (chi2 P = .006 EHBA vs. AUTOPSY, P < .001 CDC vs. AUTOPSY).
Collapse
Affiliation(s)
- K L Tyler
- Department of Neurology, University of Colorado Health Sciences Center, Denver 80262, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Abstract
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by fibro-obliterative inflammation of the entire biliary tree. It is a slowly progressive disease with an undulating course, resulting in terminal biliary cirrhosis after a median period of about 12 years after diagnosis. The etiology of the disease is unknown and there is no effective therapy that can halt disease progression. Around 8% of PSC patients develop cholangiocarcinoma, which, by the time it is diagnosed, cannot be treated curatively. The purpose of this article is to review the current knowledge about primary sclerosing cholangitis and to speculate on future strategies to address the issues of etiology and therapy.
Collapse
Affiliation(s)
- C I Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | | |
Collapse
|
|
24
|
Marotta PJ, LaRusso NF, Wiesner RH. Sclerosing cholangitis. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1997; 11:781-800. [PMID: 9512810 DOI: 10.1016/s0950-3528(97)90021-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease whose aetiopathogenesis is unknown. PSC is frequently associated with inflammatory bowel disease, in particular chronic ulcerative colitis, is most commonly observed in young males and is clinically characterized by fatigue, pruritus and jaundice. The diagnosis is supported by a cholestatic biochemical profile and histological abnormalities, and confirmed by visualization of an abnormal biliary tree. The natural history of the disease is currently being evaluated but is generally recognized to be slowly progressive, leading to complications of chronic cholestasis, portal hypertension and biliary cirrhosis. There is no specific medical treatment, and orthotopic liver transplantation remains the only definitive treatment for patients with end-stage PSC. A more rational approach to medical therapy will ensue upon a better understanding of the aetiopathogenesis of this disease.
Collapse
Affiliation(s)
- P J Marotta
- Division of Liver Transplantation, Mayo Clinic, Rochester, MN 55905, USA
| | | | | |
Collapse
|
|
25
|
Abstract
The majority of cholestatic liver diseases can be diagnosed with a carefully performed history taking, physical examination, and appropriate imaging studies. In a minority of cases, however, liver biopsy may be necessary to establish the diagnosis. In addition to the treatment of the specific liver disease, therapy should address the management of complications unique to cholestasis and progressive liver failure.
Collapse
Affiliation(s)
- T M Pasha
- Mayo Clinic, Rochester, Minnesota 55905, USA
| | | |
Collapse
|
|
26
|
|
|
27
|
Abstract
OBJECTIVE To describe primary sclerosing cholangitis (PSC) and its associated complications, as well as medical and surgical treatment. DESIGN A review of PSC and its associated etiopathologic factors is presented; numerous studies of agents that are used to treat patients with PSC are discussed. RESULTS PSC, a slowly progressive disease that often involves autoimmune damage to the biliary tree, is frequently associated with inflammatory bowel disease, usually chronic ulcerative colitis. Long-term follow-up of patients with PSC has revealed a high incidence of colon cancer and bile duct cancer, both of which are most likely related to the chronic inflammation involving these two organs. Although PSC is an unusual disease, it is now diagnosed with approximately the same frequency as is primary biliary cirrhosis. The histopathologic evolution of PSC results in irreversible damage to bile ducts, which ultimately leads to cholestasis, cirrhosis, liver failure, and premature death from liver failure unless liver transplantation is performed. Therefore, the best chance of achieving success is to treat patients with early-stage disease rather than those with irreversible end-stage cirrhotic disease. Although several medical therapies for PSC have been evaluated, only D-penicillamine, cyclosporine, methotrexate, and, most recently, ursodeoxycholic acid have been studied in controlled clinical trials. Furthermore, several surgical therapies for PSC and its associated complications have been assessed. CONCLUSION Currently, no therapy achieves a complete clinical, biochemical, or histologic remission in this disease. Until the etiopathogenesis of PSC is further defined, effective therapy is unlikely to be found. Thus, liver transplantation will continue to be an important therapeutic intervention for the management of patients with end-stage PSC.
Collapse
Affiliation(s)
- R H Wiesner
- Division of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, MN 55905
| |
Collapse
|
|
28
|
Affiliation(s)
- Y Ueno
- Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905
| | | |
Collapse
|
|
29
|
Boberg KM, Lundin KE, Schrumpf E. Etiology and pathogenesis in primary sclerosing cholangitis. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1994; 204:47-58. [PMID: 7824878 DOI: 10.3109/00365529409103625] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The etiology and pathogenesis of the inflammatory and fibrotic bile duct lesions characteristic of primary sclerosing cholangitis (PSC) is unknown, but several lines of evidence support the contention that genetic and immunologic factors are involved. There is an association with human leukocyte antigens (HLA) with an increased frequency of DR3, DR6, and DR2 positive haplotypes. DRB3*0101(DR52a) is the most strongly associated allele in some studies, but the HLA gene conferring the primary HLA associated susceptibility to PSC remains to be established. There is an aberrant expression of HLA class II antigens (DR and DP) on bile duct epithelial cells, with the potential to present antigens to the surrounding T-lymphocytes. A defective suppressor T-cell function has been suggested in some studies. The patients may have elevated levels of circulating immune complexes, immunoglobulins, and non-organ-specific autoantibodies. Antibodies to perinuclear antigens (pANCA) are present in about 80% of cases. Increased metabolism of complement C3, reduced clearance of immune complexes, and increased concentration of biliary immune complexes have been found. The strong association between PSC and ulcerative colitis (UC) has not been explained. The detection of circulating IgG antibodies against a specific epitope shared by epithelial cells in the bile ducts and colon in about two-thirds of PSC patients may be of importance. Portal bacteremia secondary to a diseased bowel may possibly contribute to development of liver disease in UC. Viral infections and toxic and ischemic factors have also been implicated in the pathogenesis of PSC. In conclusion, PSC seems to occur in genetically predisposed individuals, mediated by immunologic mechanisms. The primary event triggering the disease development is, however, unknown.
Collapse
Affiliation(s)
- K M Boberg
- Medical Dept. A, Rikshospitalet, Oslo, Norway
| | | | | |
Collapse
|
|
30
|
Affiliation(s)
- R W Chapman
- Department of Gastroenterology, John Radcliffe Hospital, Oxford
| |
Collapse
|
|
31
|
Piccoli DA, Witzleben CL, Guico CJ, Morrison A, Rubin DH. Synergism between hepatic injuries and a nonhepatotropic reovirus in mice. Enhanced hepatic infection and death. J Clin Invest 1990; 86:1038-45. [PMID: 2170443 PMCID: PMC296830 DOI: 10.1172/jci114806] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Reovirus type 1, after intravenous inoculation in the adult mouse, is secreted via bile into the intestine in an infectious form. Although reovirus type 1 is rapidly removed from systemic circulation by the liver and the lung, very few hepatocytes express reovirus antigen during infection. In intestinal cells, reovirus replicates selectively in the crypts. This site preference may be due to active cell proliferation in the crypts. We hypothesized that the state of the cell may affect virus replication and tested this hypothesis by using chemical and surgical means to increase hepatic mitotic activity. Adult mice were treated with carbon tetrachloride or surgical trauma, inoculated with reovirus type 1 intravenously, and subsequently killed. Virus antigen was identified using a highly specific immunohistochemical technique. Liver sections were stained using immunoperoxidase with specific rabbit antireovirus antibody. Hepatotoxin and surgical trauma increase reovirus antigen detection in both Kupffer cells and hepatocytes. Only the sequential administration of CCl4 and virus caused mortality at doses sublethal for each alone. These data demonstrate a synergism between hepatic injury and reovirus which results in a significant increase in the magnitude of viral infection and contributes to mortality. Such synergism may be important in idiopathic liver disease.
Collapse
Affiliation(s)
- D A Piccoli
- Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Pennsylvania
| | | | | | | | | |
Collapse
|
|
32
|
Abstract
Primary sclerosing cholangitis is an increasingly recognized chronic cholestatic liver disease. It frequently occurs in association with chronic ulcerative colitis and is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. The cause is unknown, although many mechanisms have been considered, including infectious, toxic, and immunologic. The prognosis varies. No adequate treatment exists, although a number of potential treatments have been evaluated in uncontrolled trials, and the results of controlled trials have only recently been reported. Liver transplantation has recently been shown to be an effective treatment for end-stage disease. These various advances in our understanding of primary sclerosing cholangitis are reviewed.
Collapse
Affiliation(s)
- K D Lindor
- Department of Diagnostic Radiology, Mayo Clinic, Rochester, Minnesota 55905
| | | | | | | | | |
Collapse
|