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Dutta A, Ghosh R, Pandit A, Ray A, Bhattacharya D, Chakraborty A, Chakraborty U, Dubey S, Benito-León J. Cerebral Venous Thrombosis as The Sole Presenting Manifestation of Human Immunodeficiency Virus and Hepatitis B Virus Co-Infection. MEDICAL RESEARCH ARCHIVES 2022; 10:3197. [PMID: 36382206 PMCID: PMC9648704 DOI: 10.18103/mra.v10i10.3197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cerebral venous thrombosis (CVT) following either human immunodeficiency virus (HIV) infection or hepatitis B virus (HBV) infection is a very rare condition. Moreover, it has never been reported as the presenting manifestation of HIV and HBV co-infection, even more so when the patient had a normal CD4 count and no demonstrable opportunistic infections. We aimed to report the first case of an adult Indian male, an intravenous drug abuser who developed CVT as the presenting manifestation of HIV-HBV co-infection. METHODS Patient data were obtained from medical records from the Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India. RESULTS A 25-year-old male with a history of intravenous drug abuse and a normal CD4 count developed CVT as the presenting manifestation of HIV-HBV co-infection. His CD4 count was normal, and he had no demonstrable opportunistic infections. He had an uneventful recovery of the condition (CVT) following the institution of conventional anticoagulation therapy alongside anti-retroviral therapy. CONCLUSION Whether illicit drug abuse or HIV/HBV infection itself or all in combination led to this thrombotic event cannot be precisely established. Notwithstanding, we recommend serologic testing for HIV and HBV in patients suffering from CVT with high-risk behavior.
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Affiliation(s)
- Ajitava Dutta
- Department of Neuromedicine, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India
| | - Ritwik Ghosh
- Department of General Medicine, Burdwan Medical College, and Hospital, Burdwan, West Bengal, India
| | - Alak Pandit
- Department of Neuromedicine, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India
| | - Adrija Ray
- Department of General Medicine RG Kar Medical College, and Hospital, Kolkata, West Bengal, India
| | - Dwaipayan Bhattacharya
- Department of Neuromedicine, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India
| | - Arkaprava Chakraborty
- Department of Neuromedicine, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India
| | - Uddalak Chakraborty
- Department of Neuromedicine, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India
| | - Souvik Dubey
- Department of Neuromedicine, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research & SSKM Hospital, Kolkata, West Bengal, India
| | - Julián Benito-León
- Department of Neurology, University Hospital “12 de Octubre”, Madrid, Spain;,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;,Department of Medicine, Complutense University, Madrid, Spain,
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Weber S, Bardin N. Auto-anticorps anti-phospholipides et Covid-19. REVUE FRANCOPHONE DES LABORATOIRES 2022; 2022:70-75. [PMID: 35663492 PMCID: PMC9153336 DOI: 10.1016/s1773-035x(22)00218-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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3
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IgA anti-beta-2 glycoprotein I antibodies in chronic hepatitis C. Arab J Gastroenterol 2022; 23:26-31. [DOI: 10.1016/j.ajg.2021.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/13/2021] [Accepted: 12/09/2021] [Indexed: 11/20/2022]
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Abstract
PURPOSE OF REVIEW Infections play a role in the pathogenesis of autoimmune diseases (AID). Several bacterial and viral pathogens play a double role, as both inducers and inhibitors of AID. In this review, we will present current evidence and discuss different aspects of this notion. RECENT FINDINGS Infectors that both inhibit and induce AID include Helicobacter pylori, Klebsiella pneumoniae, hepatitis B virus, group B Coxsackieviruses, Epstein-Barr virus and Lymphocytic choriomeningitis virus. Numerous AID are affected by infections, including polyarteritis nodosa, inflammatory bowel disease, and type 1 diabetes. Some pathogens, such as group B Coxsackieviruses, may induce and inhibit the development of the same AID. This reveals a complex role of infections in autoimmunity pathogenesis. SUMMARY Elucidating the exact role of each pathogen on each specific AID is important, as this will enable evaluating the manipulation of these infections in the treatment of AID.
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Mendoza-Pinto C, García-Carrasco M, Cervera R. Role of Infectious Diseases in the Antiphospholipid Syndrome (Including Its Catastrophic Variant). Curr Rheumatol Rep 2018; 20:62. [PMID: 30123926 DOI: 10.1007/s11926-018-0773-x] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW The antiphospholipid syndrome (APS) is characterized by the development of thrombotic events and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). An infectious etiology for this syndrome has been postulated. The present review is aimed to summarize recent evidence about the role of infections and vaccines in the pathogenesis of the APS (including its catastrophic variant). RECENT FINDINGS There is an increased risk of developing aPL in various infections, particularly in viral infections. The most frequent infection related to aPL has been hepatitis C virus. These antibodies may be associated with thromboembolic events, including catastrophic APS. There is a link between vaccinations, such as the tetanus toxoid and aPL, due to molecular mimicry between the two molecules. Accumulated evidence supports that the presence of aPL is associated with a variety of infections, including viruses, bacteria, fungi, and parasites, and the main mechanism to explain this correlation is molecular mimicry. Moreover, a link between vaccinations, such as the tetanus toxoid, and APS has also been described.
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Affiliation(s)
- Claudia Mendoza-Pinto
- Systemic Autoimmune Diseases Research Unit, UMAE CMN Manuel Avila Camacho, Instituto Mexicano del Seguro Social, Puebla, Mexico
- Immunology and Rheumatology, Medical School, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Mario García-Carrasco
- Systemic Autoimmune Diseases Research Unit, UMAE CMN Manuel Avila Camacho, Instituto Mexicano del Seguro Social, Puebla, Mexico
- Immunology and Rheumatology, Medical School, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Ricard Cervera
- Department of Autoimmune Diseases, Hospital Clinic, Villarroel, 170, 08036, Barcelona, Catalonia, Spain.
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Abdel-Wahab N, Talathi S, Lopez-Olivo MA, Suarez-Almazor ME. Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis. Lupus 2017; 27:572-583. [PMID: 28945149 DOI: 10.1177/0961203317731532] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Objective The objective of this paper is to conduct a systematic review and meta-analysis on the risk of developing elevated antiphospholipid (aPL) antibodies and related thromboembolic and/or pregnancy events following a viral infection. Method We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane Central Register of Controlled Trials through June 2016. Independent observational studies of elevated aPL antibodies in patients with a viral infection compared with controls or patients with lupus were included. Results We analyzed 73 publications for 60 studies. Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) were most commonly reported. Compared with healthy controls, patients with HIV were more likely to develop elevated anticardiolipin (aCL) antibodies (risk ratio (RR) 10.5, 95% confidence interval (CI) 5.6-19.4), as were those with HCV (RR 6.3, 95% CI 3.9-10.1), hepatitis B virus (HBV) (RR 4.2, 95% CI 1.8-9.5), and Epstein-Barr virus (EBV) (RR 10.9 95% CI 5.4-22.2). The only statistically significant increased risk for anti-β2-glycoprotein I (anti-β2-GPI) antibodies was observed in patients with HCV (RR 4.8 95% CI 1.0-22.3). Compared with patients with lupus, patients with HIV were more likely to develop elevated aCL antibodies (RR 1.8, 95% CI 1.3-2.6), and those with EBV, elevated anti-β2-GPI antibodies (RR 2.2, 95% CI 1.3-3.9). Thromboembolic events were most prevalent in patients with elevated aPL antibodies who had HCV (9.1%, 95% CI 3.0-18.1), and HBV (5.9%, 95% CI 2.0-11.9) infections, and pregnancy events were most prevalent in those with parvovirus B19 (16.3%, 95% CI 0.78-45.7). However, compared to virus-infected patients with negative aPL antibodies, the only statistically significant increased risk was observed in those with HCV and positive aPL. Conclusions Viral infection can increase the risk of developing elevated aPL antibodies and associated thromboembolic events. Results are contingent on the reported information.
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Affiliation(s)
- N Abdel-Wahab
- 1 Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The 4002 University of Texas MD Anderson Cancer Center , Houston, TX, USA.,2 Rheumatology and Rehabilitation Department, Assiut University Hospitals, Faculty of Medicine, Assiut, Egypt
| | - S Talathi
- 3 2011 Lincoln Medical Center , Weill Cornell Medical College, Bronx, NY, USA
| | - M A Lopez-Olivo
- 1 Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The 4002 University of Texas MD Anderson Cancer Center , Houston, TX, USA
| | - M E Suarez-Almazor
- 1 Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The 4002 University of Texas MD Anderson Cancer Center , Houston, TX, USA
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Thrombocytopenia in Patients with Chronic Hepatitis C Virus Infection. Mediterr J Hematol Infect Dis 2017; 9:e2017019. [PMID: 28293407 PMCID: PMC5333732 DOI: 10.4084/mjhid.2017.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 02/07/2017] [Indexed: 12/11/2022] Open
Abstract
Thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection is a major problem. The pathophysiology is multifactorial, with auto-immunogenicity, direct bone marrow suppression, hypersplenism, decreased production of thrombopoietin and therapeutic adverse effect all contributing to thrombocytopenia in different measures. The greatest challenge in the care of chronic HCV patients with thrombocytopenia is the difficulty in initiating or maintaining IFN containing anti-viral therapy. Although at present, it is possible to avoid this challenge with the use of the sole Direct Antiviral Agents (DAAs) as the primary treatment modality, thrombocytopenia remains of particular interest, especially in cases of advanced liver disease. The increased risk of bleeding with thrombocytopenia may also impede the initiation and maintenance of different invasive diagnostic and therapeutic procedures. While eradication of HCV infection itself is the most practical strategy for the remission of thrombocytopenia, various pharmacological and non-pharmacological therapeutic options, which vary in their effectiveness and adverse effect profiles, are available. Sustained increase in platelet count is seen with splenectomy and splenic artery embolization, in contrast to only transient rise with platelet transfusion. However, their routine use is limited by complications. Different thrombopoietin analogues have been tried. The use of synthetic thrombopoietins, such as recombinant human TPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMDGF), has been hampered by the development of neutralizing antibodies. Thrombopoietin-mimetic agents, in particular, eltrombopag and romiplostim, have been shown to be safe and effective for HCV-related thrombocytopenia in various studies, and they increase platelet count without eliciting any immunogenicity Other treatment modalities including newer TPO analogues-AMG-51, PEG-TPOmp and AKR-501, recombinant human IL-11 (rhIL-11, Oprelvekin), recombinant human erythropoietin (rhEPO), danazol and L-carnitine have shown promising early result with improving thrombocytopenia. Thrombocytopenia in chronic HCV infection remain a major problem, however the recent change in DAAs without IFN, as the frontline therapy for HCV, permit to avoid the dilemmas associated with initiating or maintaining IFN based anti-viral therapy.
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8
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Peterson LK, Willis R, Harris EN, Branch WD, Tebo AE. Antibodies to Phosphatidylserine/Prothrombin Complex in Antiphospholipid Syndrome: Analytical and Clinical Perspectives. Adv Clin Chem 2016; 73:1-28. [PMID: 26975968 DOI: 10.1016/bs.acc.2015.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy-related morbidity accompanied by persistently positive antiphospholipid antibodies (aPL). Current laboratory criteria for APS classification recommend testing for lupus anticoagulant as well as IgG and IgM anticardiolipin, and beta-2 glycoprotein I (anti-β2GPI) antibodies. However, there appears to be a subset of patients with classical APS manifestations who test negative for the recommended criteria aPL tests. While acknowledging that such patients may have clinical features that are not of an autoimmune etiology, experts also speculate that these "seronegative" patients may test negative for relevant autoantibodies as a result of a lack of harmonization and/or standardization. Alternatively, they may have aPL that target other antigens involved in the pathogenesis of APS. In the latter, autoantibodies that recognize a phosphatidylserine/prothrombin (PS/PT) complex have been reported to be associated with APS and may have diagnostic relevance. This review highlights analytical and clinical attributes associated with PS/PT antibodies, taking into consideration the performance characteristics of criteria aPL tests in APS with specific recommendations for harmonization and standardization efforts.
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Affiliation(s)
- Lisa K Peterson
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Rohan Willis
- Rheumatology/Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
| | | | - Ware D Branch
- Maternal Fetal Medicine, University of Utah and Intermountain Healthcare, Salt Lake City, Utah, USA
| | - Anne E Tebo
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA; ARUP Laboratories, Institute of Clinical and Experimental Pathology, Salt Lake City, Utah, USA.
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9
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Abstract
Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild.
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Affiliation(s)
- E Rosenthal
- Service de Médecine Interne, Hôpital de l'Archet, CHU de Nice, Nice; Université de Nice-Sophia Antipolis, Nice, France COREVIH PACA EST, CHU de Nice, France
| | - P Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France INSERM, UMR_S 959, Paris, France CNRS, FRE3632, Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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10
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Autoimmune reactions in the course of the hepatitis C virus (HCV) infection. Clin Exp Hepatol 2015; 1:39-43. [PMID: 28856254 PMCID: PMC5497407 DOI: 10.5114/ceh.2015.51804] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 05/21/2015] [Indexed: 02/08/2023] Open
Abstract
The immune response to the presence of the virus, both specific and non-specific, plays a decisive role in the natural history of the infection, and influences the intensity of lesions in the liver. Despite the great progress which we were able to observe over the last several years, many issues still require clarification. The problem of autoimmune reactions during hepatitis C virus (HCV) infection includes at least two issues. First, the risk of exacerbating reactions against the organism’s own tissues that existed before the treatment. There is also an increased risk of the development of de novo autoimmune reactions, triggered mostly by interferon α. Hepatitis C virus infection predisposes to the development of diseases characterised as being certainly or probably immune-mediated. Currently the situation has changed due to introducing non-interferon therapies for HCV treatment, which eliminate the risk associated with immunotherapy in patients with autoimmune diseases, yet the therapies are not widely available.
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11
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Ambrosino P, Lupoli R, Tarantino P, Di Minno A, Tarantino L, Di Minno MND. Viral hepatitis and anti-phospholipid antibodies positivity: A systematic review and meta-analysis. Dig Liver Dis 2015; 47:478-87. [PMID: 25835772 DOI: 10.1016/j.dld.2015.03.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Revised: 03/04/2015] [Accepted: 03/09/2015] [Indexed: 02/09/2023]
Abstract
BACKGROUND Anti-phospholipid antibodies positivity is associated with several clinical conditions, including infectious diseases. AIMS We performed a meta-analysis evaluating the association of hepatitis B and C with anti-phospholipid antibody positivity and with anti-phospholipid antibody-related thrombotic complications. METHODS Studies evaluating the association of viral hepatitis with anti-cardiolipin, anti-β2 glycoprotein-I and lupus anticoagulant antibodies and anti-phospholipid antibody-related thrombotic events were systematically searched. RESULTS 20 studies (2319 cases, 1901 controls) were included. The analyses showed that viral hepatitis is associated with the presence of anti-cardiolipin and anti-β2 glycoprotein-I antibodies. The association with anticardiolipin antibodies was confirmed in both hepatitis B (OR 11.22, 95% CI: 6.68-18.84) and hepatitis C (OR 11.26, 95% CI: 6.82-18.59). Similarly, compared to controls, anti-β2 glycoprotein-I antibodies were found more frequently in hepatitis B (OR 14.07, 95% CI: 3.06-64.66) and hepatitis C (OR 5.64, 95% CI: 1.69-18.77). Moreover, 11 studies (257 cases, 1079 controls) showed a higher prevalence of venous and/or arterial thrombosis in patients with hepatitis and anti-cardiolipin antibody positivity compared hepatitis alone (OR 3.29, 95% CI: 1.79-6.07). This result was consistently confirmed in hepatitis C (OR 3.64, 95% CI: 1.78-7.46) but not in hepatitis B. CONCLUSIONS Viral hepatitis is significantly associated with anti-phospholipid antibody positivity and with anti-phospholipid antibody-related thrombotic complications.
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Affiliation(s)
- Pasquale Ambrosino
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Roberta Lupoli
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Paolo Tarantino
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Alessandro Di Minno
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Luciano Tarantino
- Department of Surgery, Interventional Hepatology Unit, Andrea Tortora Hospital, Pagani, Italy
| | - Matteo Nicola Dario Di Minno
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy; Unit of Cell and Molecular Biology in Cardiovascular Diseases, Centro Cardiologico Monzino, IRCCS, Milan, Italy.
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12
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Autoimmune hepatitis in patients with chronic HBV and HCV infections: patterns of clinical characteristics, disease progression and outcome. Ann Hepatol 2014. [PMID: 24378276 DOI: 10.1016/s1665-2681(19)30914-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
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13
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Blank M, Israeli E, Shoenfeld Y. When APS (Hughes syndrome) met the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Lupus 2012; 21:711-4. [PMID: 22635209 DOI: 10.1177/0961203312438115] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Vaccination of healthy individuals is the most effective approach to protect the public from infections and prevent the spread of many infectious diseases all over the globe. Licensed vaccines are mostly safe, but in rare cases they may be associated with humoral response to self-antigens due to molecular mimicry, epitope spread, bystander activation or polyclonal triggering. Moreover, the clinical picture of autoimmune conditions following post-vaccination is rarer. Nevertheless, anecdotal case reports on the flare of autoimmune response with clinical manifestations were reported. Herein, we discuss this topic in relation to post-vaccination-induced antiphospholipid antibodies following tetanus toxoid vaccine, HBV and influenza associated in rare cases with antiphospholipid syndrome clinical manifestations. We will discuss the possible mechanisms which pertain to ASIA (Shoenfeld syndrome).
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Affiliation(s)
- M Blank
- Zabludowitz Center for Autoimmune Diseases, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel
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14
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Maharshak N, Halfon P, Deutsch V, Peretz H, Berliner S, Fishman S, Zelber-Sagi S, Rozovski U, Leshno M, Oren R. Increased fibrosis progression rates in hepatitis C patients carrying the prothrombin G20210A mutation. World J Gastroenterol 2011; 17:5007-13. [PMID: 22174551 PMCID: PMC3236579 DOI: 10.3748/wjg.v17.i45.5007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 04/10/2011] [Accepted: 04/17/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine whether hepatitis C virus (HCV)-infected patients who carry hypercoagulable mutations suffer from increased rates of liver fibrosis.
METHODS: We analyzed DNA samples of 168 HCV patients for three common hypercoagulable gene mutations: prothrombin 20210 (PT20210), factor V Leiden (FV Leiden) and methylene tetrahydrofolate reductase (MTHFR). The patients were consecutively recruited as part of the prospective “Fibroscore Study” in France. The effect of the various mutations on the rate of fibrosis was analyzed statistically and was correlated with epidemiological, clinical and biochemical data such as grade and stage of liver biopsies, patients’ risk factors for liver cirrhosis, and timing of infection.
RESULTS: Fifty two of the patients were categorized as “fast fibrosers” and 116 as “slow fibrosers”; 13% of the “fast fibrosers” carried the PT20210 mutation as compared with 5.5% of the “slow fibrosers”, with an odds ratio of 4.76 (P = 0.033; 95% CI: 1.13-19.99) for “fast” liver fibrosis. Carriage of MTHFR or FV Leiden mutations was not associated with enhanced liver fibrosis.
CONCLUSION: Carriage of the PT20210 mutation is related to an increased rate of liver fibrosis in HCV patients.
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15
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Palazzi C, Buskila D, D'Angelo S, D'Amico E, Olivieri I. Autoantibodies in patients with chronic hepatitis C virus infection: pitfalls for the diagnosis of rheumatic diseases. Autoimmun Rev 2011; 11:659-63. [PMID: 22155016 DOI: 10.1016/j.autrev.2011.11.011] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2011] [Accepted: 11/22/2011] [Indexed: 12/29/2022]
Abstract
Hepatitis C virus infection (HCV) is one of the best mimes in medicine. About 40-70% of patients suffering from this disorder develop at least one extra-hepatic disorder that can have a rheumatic nature (arthralgias, arthritis, vasculitis and sicca syndrome) and must be differentiated from the primitive rheumatic diseases. In addition, HCV infection can also alter the laboratory tests. Several alterations of first line laboratory tests can be usually found in both chronic HCV infection and chronic inflammatory rheumatic disorders. In the present review we analyze the interference of HCV in tests more specifically used in rheumatology: rheumatoid factor and other autoantibodies (ANA, anti-ENA, ANCA, anti-DNA, antiphospholipid, anti-CCP). In patients suffering from HCV infection, the diagnosis of connective tissue diseases (CTD) or rheumatoid arthritis (RA) should be made only when the detected symptoms or laboratory data are not inducible by HCV, otherwise only a diagnosis of "possible CTD" or "possible RA" should be considered.
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Affiliation(s)
- Carlo Palazzi
- Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Italy.
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16
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Borg BB, Seetharam A, Subramanian V, Ilias H, Lisker–Melman M, Korenblat K, Anderson C, Shenoy S, Chapman WC, Crippin JS, Mohanakumar T. Immune response to extracellular matrix collagen in chronic hepatitis C-induced liver fibrosis. Liver Transpl 2011; 17:814-23. [PMID: 21425431 PMCID: PMC3700355 DOI: 10.1002/lt.22303] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus (HCV) infection and its recurrence after orthotopic liver transplantation (OLT) are associated with the remodeling of extracellular matrix (ECM) components [particularly collagen (Col)], which leads to fibrosis. Our aim was to determine whether the development of antibodies (Abs) to self-antigen Col in HCV-infected patients correlates with the fibrosis stage and the peripheral cytokine response. Patients with chronic HCV infection, patients with HCV recurrence after OLT who had undergone a biopsy procedure, and healthy control subjects were enrolled. The HCV subjects (n = 70) were stratified as follows: (1) a non-OLT group without fibrosis (Scheuer stages 0-2), (2) a non-OLT group with fibrosis (Scheuer stages 3-4), (3) a post-OLT group without fibrosis (Scheuer stages 0-2), and (4) a post-OLT group with fibrosis (Scheuer stages 3-4). Serum samples were analyzed for Abs against Col1, Col2, Col4, Col5, and vimentin with enzyme-linked immunosorbent assays. Serum levels of cytokines were measured with multiplex bead immunoassays. The levels of Abs to Col1 were higher in the fibrosis groups versus the no-fibrosis groups and the controls for both non-OLT patients (P < 0.001) and post-OLT patients (P = 0.01). There were increased levels of Abs to Col2, Col4, Col5, and vimentin in the non-OLT fibrosis group (Col2, P = 0.0001; Col4, P = 0.122; Col5, P < 0.0001; vimentin, P = 0.36) and in the post-OLT fibrosis group (Col2, P = 0.006; Col4, P = 0.19; Col5, P < 0.0001; vimentin, P = 0.24) in comparison with the no-fibrosis groups. The non-OLT and post-OLT fibrosis groups demonstrated significantly higher T helper 2 (T(h) 2) and T helper 17 (T(h) 17) cytokine levels and lower T helper 1 cytokine levels in comparison with the no-fibrosis groups. Our results demonstrate that in HCV-infected patients, the levels of Abs to ECM Col1, Col2, and Col5 positively correlate with liver fibrosis, which is associated with a predominantly T(h) 2 and T(h) 17 cytokine profile.
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Affiliation(s)
- Brian B. Borg
- Department of Medicine, Washington University School of Medicine St. Louis, MO 63110
| | - Anil Seetharam
- Department of Medicine, Washington University School of Medicine St. Louis, MO 63110
| | - Vijay Subramanian
- Department of Surgery, Washington University School of Medicine St. Louis, MO 63110
| | - Haseeb Ilias
- Department of Surgery, Washington University School of Medicine St. Louis, MO 63110
| | | | - Kevin Korenblat
- Department of Medicine, Washington University School of Medicine St. Louis, MO 63110
| | - Christopher Anderson
- Department of Surgery, Washington University School of Medicine St. Louis, MO 63110
| | - Surendra Shenoy
- Department of Surgery, Washington University School of Medicine St. Louis, MO 63110
| | - William C. Chapman
- Department of Surgery, Washington University School of Medicine St. Louis, MO 63110
| | - Jeffrey S. Crippin
- Department of Medicine, Washington University School of Medicine St. Louis, MO 63110
| | - Thalachallour Mohanakumar
- Department of Surgery, Washington University School of Medicine St. Louis, MO 63110,Department of Pathology and Immunology, Washington University School of Medicine St. Louis, MO 63110
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Huh JY, Yi DY, Hwang SG, Choi JJ, Kang MS. Characterization of antiphospholipid antibodies in chronic hepatitis B infection. THE KOREAN JOURNAL OF HEMATOLOGY 2011; 46:36-40. [PMID: 21461302 PMCID: PMC3065625 DOI: 10.5045/kjh.2011.46.1.36] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Revised: 02/13/2011] [Accepted: 02/15/2011] [Indexed: 11/17/2022]
Abstract
BACKGROUND Many infections are associated with antiphospholipid antibodies (aPLs). The purpose of this study was to investigate the prevalence, persistence, clinical significance, and characteristics of aPLs in hepatitis B virus (HBV)-infected patients. METHODS This study included 143 patients with HBV infection and 32 healthy individuals as controls. The presence of anticardiolipin antibodies (aCL Ab), anti-β(2)-glycoprotein I antibodies (β(2)GPI Ab), and lupus anticoagulant (LA) was assessed. RESULTS The total prevalence of aPLs in HBV-infected patients was 12.6% (18 of 143). Of these 18 patients, 15 had low to medium titers of aCL Ab (10 with IgM, 4 with IgG, and 1 with both isotypes). β(2)GPI Ab and LA were detected in 3 (2.1%) and 2 (1.4%) patients with HBV infection, respectively. In follow-up specimens from 14 patients with elevated levels of aCL Ab or β(2)GPI Ab, 10 (71.4%) showed the persistent presence of aPLs. No clinical manifestations related to aPLs were identified. CONCLUSION In HBV-infected patients, the most frequently detected antiphospholipid antibodies were IgM aCL Ab, which have a weak association with the clinical manifestations of APS. Unlike the transient presence reported for other infection-associated aPLs, most aPLs were persistently detected over a 12-week period in patients with HBV infection.
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Affiliation(s)
- Ji Young Huh
- Department of Laboratory Medicine, CHA Bundang Medical Center, Seongnam, Korea
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18
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Louie KS, Micallef JM, Pimenta JM, Forssen UM. Prevalence of thrombocytopenia among patients with chronic hepatitis C: a systematic review. J Viral Hepat 2011; 18:1-7. [PMID: 20796208 DOI: 10.1111/j.1365-2893.2010.01366.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Thrombocytopenia (TCP) is a haematological condition known to occur in chronically infected hepatitis C (HCV) patients and may interfere with diagnostic procedures, such as liver biopsy, because of risk of bleeding. It may also exclude patients from effective antiviral treatment. We conducted a systematic literature review of articles and conference abstracts, to assess the prevalence of TCP among those with HCV and to describe demographics, liver disease stage and treatment characteristics of these patients. Studies of individuals with confirmed chronic HCV infection were included in the review if the study had a clear definition of thrombocytopenia and a sample size of at least 50 subjects. The final selection included 27 studies (21 articles and six abstracts). The definitions of thrombocytopenia varied between studies and were based either on platelet counts, with threshold levels ranging between ≤ 100 × 10(9) and ≤ 180 × 10(9) /L, or on criteria set in haematological guidelines. The prevalence of TCP ranged from 0.16% to 45.4% and more than half of the studies reported a TCP prevalence of 24% or more. Because of the different TCP definitions, heterogeneity in study design and insufficient data on study characteristics such as age, gender, HCV treatment rates and disease severity an overall summary estimate of TCP prevalence among patients with HCV was not feasible. However, the relatively large prevalence in the majority of the studies suggests that there may be a substantial number of HCV patients at risk of bleeding complications and reduced likelihood of successful HCV antiviral treatment.
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Affiliation(s)
- K S Louie
- Worldwide Epidemiology, GlaxoSmithKline, Stockley Park, Middlesex, UK
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19
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Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol 2010; 8:1017-29. [PMID: 20870037 DOI: 10.1016/j.cgh.2010.08.026] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Revised: 08/20/2010] [Accepted: 08/24/2010] [Indexed: 02/06/2023]
Abstract
In addition to its effects in the liver, chronic hepatitis C virus (HCV) infection can have serious consequences for other organ systems. Extrahepatic manifestations include mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production; reductions in quality of life involve fatigue, depression, and cognitive impairment. MC vasculitis, certain types of lymphoma, insulin resistance, and cognitive function appear to respond to anti-HCV therapy. However, treatments for HCV and other biopsychosocial factors can reduce quality of life and complicate management. HCV treatment has a high overall cost that increases when extrahepatic manifestations are considered. HCV appears to have a role in the pathogenesis of MC vasculitis, certain types of lymphoma, and insulin resistance. Clinicians who treat patients with HCV infections should be aware of potential extrahepatic manifestations and how these can impact and alter management of their patients.
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Affiliation(s)
- Ira M Jacobson
- Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021, USA.
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20
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Enomoto M, Negoro N, Fujii H, Kobayashi S, Iwai S, Morikawa H, Tamori A, Sakaguchi H, Habu D, Shiomi S, Kawada N. Hepatitis B-associated cryoglobulinemia and antiphospholipid antibodies. KANZO 2010; 51:454-456. [DOI: 10.2957/kanzo.51.454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/08/2023]
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Moorman J, Dong ZP, Ni L, Zhang C, Borthwick T, Yao ZQ. Abnormal B-cell activation associated with TALL-1 over-expression and SOCS-1 suppression during chronic hepatitis C virus infection. Immunology 2009; 128:227-35. [PMID: 19740379 DOI: 10.1111/j.1365-2567.2009.03106.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is associated with cirrhosis, autoimmunity and lymphoproliferative disorders. We have previously reported a differential regulation of T and B lymphocytes by HCV core protein in vitro. In this report, we employed a translational approach to characterize the activation status of peripheral B cells from individuals with chronic HCV infection and to explore potential mechanisms for B-cell dysregulation in the setting of HCV infection. In contrast to the T-cell suppression observed in HCV-infected individuals, B cells exhibit a non-specific polyclonal activation phenotype, characterized by significantly higher levels of (1) the early activation marker, CD69, (2) the costimulatory molecule, CD86, and (3) the CCR5 chemokine receptor, CD195, when compared with B cells from healthy donors in response to phytohaemagglutinin (PHA) stimulation. Importantly, tumour necrosis factor- and Apo-L-related leucocyte-expressed ligand-1 (TALL-1), also known as B-lymphocyte stimulator (BLYS), was found to be up-regulated on the surface of B cells from HCV patients in response to PHA as well as HCV core antigen stimulation. This up-regulation of TALL-1 was associated with vigorous memory B-cell responses to viral antigenic stimulation. Additionally, suppressor of cytokine signalling-1 (SOCS-1), a negative feedback immunoregulator that is inhibited in B lymphocytes by HCV core in vitro, was also inhibited in B cells from HCV patients when compared with healthy donors. These findings suggest that TALL-1 over-expression and SOCS-1 suppression are associated with aberrant B-cell activation, providing a plausible basis for the B-cell clonal expansion underlying the lymphoproliferative disorders and autoimmune phenomena observed during chronic HCV infection.
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22
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Tsironi E, Gatselis N, Kotoula MG, Zachou K, Pefkianaki M, Zacharaki F, Chatzoulis DZ, Dalekos GN. Ocular disorders as the prevailing manifestations of antiphospholipid syndrome: a case series. CASES JOURNAL 2009; 2:159. [PMID: 19946530 PMCID: PMC2783115 DOI: 10.1186/1757-1626-2-159] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2009] [Accepted: 10/20/2009] [Indexed: 11/16/2022]
Abstract
Introduction Antiphospholipid syndrome is an autoimmune disorder characterized by either a history of vascular thrombosis (one or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ) or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The systemic features of the syndrome are characterized by large variability depending on the affected organ(s). Among them, neurological and behavioural disturbances, dermatological features as livedo reticularis and renal, ocular, liver or valvular heart manifestations have been reported in antiphospholipid syndrome patients. However, studies on the frequency and clinical presentation of the ocular manifestations as the prevailing (first) sign of antiphospholipid syndrome in patients suffering from "unexplained" ocular disease are missing. Herein, we present three cases suffering from unexplained ocular disease as first manifestation of antiphospholipid syndrome. Case presentation All the three patients were referred to our department because of unexplained ocular features from the anterior or posterior segment and unexplained neuro-ophthalmologic symptoms. The first patient had bilateral retinal occlusive disease, the second and the third patient had unilateral nonarteritic anterior ischemic optic neuropathy with macular oedema. Moderate to high levels of antiphospholipid antibodies were detected in all of them at baseline as well as 6 to 12 weeks after initial testing confirming the presence of antiphospholipid antibodies. Anticoagulant treatment with acenocoumarol was instituted resulting in stabilization and/or improvement of ocular signs in all of them. Conclusion Due to the important diagnostic and therapeutic implications of antiphospholipid syndrome, the possibility of ocular features as the first clinical manifestation of antiphospholipid syndrome should be kept in mind of the physicians particularly in patients with no evident risk factors for ocular disease. In this case, prompt anticoagulant treatment and close follow-up seem to be essential for vision salvation and stabilization.
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Affiliation(s)
- Evangelia Tsironi
- Department of Ophthalmology, Medical School, University of Thessaly, Larissa, 41110, Greece.
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23
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Abstract
The etiology and pathogenesis of autoimmune diseases have long been an enigmatic subject that have involved genetic and environmental factors. Recent intriguing data has contributed to the mechanisms involved, including the relationship of infectious agents and loss of tolerance. This loss of tolerance is illustrated by the data on the immune response to Hepatitis B virus such as the molecular mimicry between HBV antigens and self proteins, the generation of immune complexes between HBV antigens and antibodies, and apoptosis/tissue damage resulting in the exposure of intracellular antigens to the immune system. In this paper, we review the current database related to HBV infection and a variety of autoimmune conditions, including autoimmune hepatitis, systemic lupus erythematosus, aplastic anemia, antiphospholipid syndrome, polyarteritis nodosa, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, thyroid disease and uveitis.
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24
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Chuang FR, Chen TC, Yang CC, Cheng YF, Hsu KT, Lee CH, Lin CL, Wang IK, Chang HW, Wang PH. IgM-Anticardiolipin Antibody and Vascular Access Thrombosis in Chronic Hemodialysis Patients. Ren Fail 2009. [DOI: 10.1081/jdi-42815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Kida Y, Maeshima E, Yamada Y. Portal vein thrombosis in a patient with hepatitis C virus-related cirrhosis complicated with antiphospholipid syndrome. Rheumatol Int 2009; 29:1495-8. [PMID: 19184031 DOI: 10.1007/s00296-009-0856-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2008] [Accepted: 01/05/2009] [Indexed: 02/02/2023]
Abstract
We report a rare case of portal vein thrombosis (PVT) associated with antiphospholipid syndrome (APS) and hepatitis C virus-related cirrhosis. A 59-year-old woman with hepatitis C virus (HCV) infection was admitted because of coma. The blood test showed a typically cirrhosis pattern including an elevated serum ammonia level. Abdominal computed tomography showed liver cirrhosis and thrombus in the right branch of the portal vein. To elucidate the cause of PVT, antiphospholipid antibodies were examined. Both IgG anti-cardiolipin antibody (ELISA) and IgG anti-cardiolipin-beta2 -glycoprotein I complex antibody (ELISA) were positive. When PVT is detected in a patient with cirrhosis, it might be necessary to examine antiphospholipid antibodies to clarify the cause of PVT.
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Affiliation(s)
- Yohei Kida
- Department of Internal Medicine, Kainan Municipal Hospital, Kainan 642-0002, Japan.
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26
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Sène D, Piette JC, Cacoub P. [Antiphospholipid antibodies, antiphospholipid syndrome and viral infections]. Rev Med Interne 2008; 30:135-41. [PMID: 18926604 DOI: 10.1016/j.revmed.2008.05.020] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Revised: 03/08/2008] [Accepted: 05/17/2008] [Indexed: 01/06/2023]
Abstract
Since the association between antiphospholipid antibodies and syphilis was first described, many other viral, bacterial and parasitic infections have been shown to induce antiphospholipid antibodies, notably anticardiolipin antibodies. These aPL are usually associated neither with anti-beta2 glycoprotein I antibodies (anti-beta2-GPI) nor with thrombotic events, even if cases of arterial and deep venous thrombosis have been reported in such circumstances. A literature review shows that anticardiolipin antibodies occur frequently in viral infections, particularly in HIV (49.8%), HBV (24%) and HCV (20%). The prevalence of anti-beta2 glycoprotein I antibodies (anti-beta2GPI) is lower (HCV: 1.7%, HIV: 5.6%, HBV: 3.3%) and there is no demonstrated association with a risk of thrombotic events or hematological manifestations defining antiphospholipid syndrome (APS). Regarding other viral infections, including viral hepatitis A, herpes virus (CMV, EBV, VZV), parvovirus B19 and HTLV-1 infections, only a few studies are available but data confirm the high prevalence of antiphospholipid antibodies at the acute phase. Finally, antiphospholipid antibodies, mainly anticardiolipin, are frequently associated with viral infections. Their presence may probably reflect an intense or chronic antigenic stimulation of the immune system. However, their evolution under antiviral therapy and correlation with the quality of the virological control and/or the immune restoration remain to be determined.
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Affiliation(s)
- D Sène
- Service de médecine interne II, groupe hospitalier La-Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75013 Paris, France.
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27
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Gabeta S, Norman GL, Gatselis N, Liaskos C, Papamichalis PA, Garagounis A, Zachou K, Rigopoulou EI, Dalekos GN. IgA anti-b2GPI antibodies in patients with autoimmune liver diseases. J Clin Immunol 2008; 28:501-511. [PMID: 18551357 DOI: 10.1007/s10875-008-9211-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2008] [Accepted: 05/19/2008] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Recently, we reported a high prevalence of immunoglobulin G and/or immunoglobulin M anticardiolipin antibodies (aCL) in patients with autoimmune liver diseases, namely, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), which were independent of the respective isotypes of antibodies against beta2-glycoprotein I (anti-b2GPI). Immunoglobulin A (IgA) aCL and IgA anti-b2GPI are the least studied of the three specific isotypes either in antiphospholipid syndrome (APS) or in other conditions. METHODS Therefore, we investigated the prevalence and clinical significance of IgA anti-b2GPI and IgA aCL by enzyme-linked immunosorbent assays in another set of Caucasian patients with autoimmune liver diseases (59 AIH, 96 PBC, and 37 PSC). The disease controls group consisted of 50 hepatitis C virus (HCV) patients, 50 hepatitis B virus (HBV), 30 alcoholic liver disease (ALD), 30 non-alcoholic steatohepatitis (NASH), and 110 healthy controls. RESULTS AND DISCUSSION IgA anti-b2GPI prevalence was higher in AIH (50.8%) compared to PBC (p = 0.005), PSC (p = 0.008), NASH (p = 0.004), ALD (p = 0.01), and HCV (p = 0.002). The titers were also significantly higher in AIH compared to any other group of the study. IgA aCL prevalence was higher in AIH (33.9%) compared to PBC (p = 0.005), PSC (p = 0.014), NASH (p = 0.001), ALD (p = 0.004), and HCV (p < 0.001). IgA anti-b2GPI or IgA aCL were not associated with APS features in patients with liver autoimmunity. Of note, IgA anti-b2GPI and IgA aCL were associated with clinical and biochemical markers of disease severity in AIH and PBC. We demonstrated a high prevalence and high titers of IgA anti-b2GPI in patients with AIH compared to any other liver disease of the study. CONCLUSION IgA anti-b2GPI and IgA aCL were associated with the severity and biochemical activity of AIH and PBC, but long-term prospective studies are needed to address whether this new finding is of clinical importance in AIH and PBC patients.
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Affiliation(s)
- Stella Gabeta
- Department of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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28
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Tsikrikoni A, Rigopoulou EI, Zachou K, Liaskos C, Kyriakou D, Dalekos GN. Bone marrow findings in patients with autoimmune liver diseases. J Gastroenterol Hepatol 2008; 23:e416-21. [PMID: 18205770 DOI: 10.1111/j.1440-1746.2008.05309.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS We have recently reported quantitative and qualitative differences of the bone marrow (BM) hematopoietic progenitor cells in autoimmune hepatitis type-1 (AIH-1) and primary biliary cirrhosis (PBC). In order to better investigate the possible involvement of BM in these diseases, we studied the morphological abnormalities of BM aspirates in the same patients with AIH-1 and PBC. METHODS BM smears from 13 AIH-1 and 13 PBC patients were investigated. BM from 12 patients with cirrhosis of non-autoimmune etiology and eight healthy individuals served as pathological (PC) and healthy controls (HC). RESULTS Erythroid, granulocyte and platelet precursors were variably altered. Polychromatic normoblasts and immature megakayocytes were higher in AIH-1 (11.9 +/- 2.9 and 16.2 +/- 16.9, respectively) and PBC (10.2 +/- 3.6 and 17.3 +/- 20.2, respectively) compared to PC (7 +/- 2 and 2.3 +/- 6.0, respectively) and HC (7.9 +/- 1.6 and 0 +/- 0, respectively) (P = 0.0001 and P = 0.006). In AIH-1, immature megakaryocytes were significantly higher in patients receiving immunosuppression (25.71 +/- 17.66 vs 5.00 +/- 5.48; P < 0.02) and were associated negatively with laboratory markers of disease activity. BM plasmacytosis was observed more frequently in AIH-1 compared to PBC and PC. BM monocytosis was found in all patients with AIH-1, PBC and PC whereas approximately half of the patients with autoimmune liver diseases and all PC had BM lymphocytosis. CONCLUSIONS BM monocytosis and lymphocytosis are commonly found in AIH-1 and PBC patients irrespective of the presence of cirrhosis or the use of immunosuppression. BM plasmacytosis appears to be a distinct finding in some AIH-1 patients, as similar findings were observed in only one PBC and one PC, whereas BM immature megakaryocytes characterize both AIH-1 and PBC. Whether BM is a target organ in AIH-1 and PBC needs further investigation.
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Affiliation(s)
- Aikaterini Tsikrikoni
- Department of Medicine, Academic Liver Unit, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Thessaly, Greece
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Delluc A, Saadoun D, Ghillani-Dalbin P, Sene D, Piette JC, Cacoub P. Cryofibrinogen in patients with hepatitis C virus infection. Am J Med 2008; 121:624-31. [PMID: 18589059 DOI: 10.1016/j.amjmed.2008.03.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 02/19/2008] [Accepted: 03/07/2008] [Indexed: 11/15/2022]
Abstract
BACKGROUND Mixed cryoglobulin is usually associated with hepatitis C virus (HCV) infection and might cause systemic vasculitis. The presence and impact of cryofibrinogen, another cryoprotein, in the serum of HCV-infected patients have not yet been evaluated. The objective was to study the prevalence and the clinical and therapeutic impacts of cryofibrinogen in HCV-infected patients. METHODS A total of 143 consecutive HCV-infected (RNA+) patients (including 57 patients with HCV-related vasculitis) were screened for cryofibrinogen and cryoglobulin (positive if >0.05 g/L). The main characteristics and outcome were evaluated according to the cryofibrinogen/cryoglobulin status at baseline. RESULTS At baseline, 53 of 143 patients (37%) were cryofibrinogen positive, most of whom (47/53 [89%]) were also cryoglobulin positive. Only 37 of 90 cryofibrinogen-negative patients (41%) were cryoglobulin positive (P<.001). In patients with HCV-related vasculitis, 28 of 57 (49%) were cryofibrinogen positive compared with 25 of 86 patients (29%) without vasculitis (P=.03). There was a higher rate of renal involvement in cryofibrinogen-negative/cryoglobulin-positive patients than in cryofibrinogen-positive/cryoglobulin-positive patients (10/25 [40%] vs 3/27 [11%], respectively; P=.02). After a mean follow-up of 32.6 months, among patients who were cryofibrinogen positive at baseline, 12 of 26 (46%) of those who received an HCV treatment were cryofibrinogen negative at the end of follow-up compared with 4 of 16 (25%) of those who did not receive antiviral drugs. Most patients who became cryofibrinogen negative also became cryoglobulin negative (93%). CONCLUSION Cryoproteins, including cryoglobulin and cryofibrinogen, are frequently found in the serum of HCV-infected patients. In such patients, a positive cryofibrinogen status is closely related to the presence of cryoglobulin at baseline and after antiviral therapy.
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Affiliation(s)
- Aurélien Delluc
- Service de Médecine Interne, Université Pierre et Marie Curie, Paris 6, France
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30
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Atta A, Estevam P, Paraná R, Pereira C, Leite B, Sousa-Atta M. Antiphospholipid antibodies in Brazilian hepatitis C virus carriers. Braz J Med Biol Res 2008; 41:489-92. [DOI: 10.1590/s0100-879x2008005000024] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2007] [Accepted: 05/26/2008] [Indexed: 12/23/2022] Open
Affiliation(s)
| | | | - R. Paraná
- Universidade Federal da Bahia, Brasil
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31
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Kashef S, Karimi M, Amirghofran Z, Ayatollahi M, Pasalar M, Ghaedian MM, Kashef MA. Antiphospholipid antibodies and hepatitis C virus infection in Iranian thalassemia major patients. Int J Lab Hematol 2008; 30:11-6. [PMID: 18190462 DOI: 10.1111/j.1751-553x.2007.00916.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Although the precise nature of Antiphospholipid antibodies is still not clearly defined, they are known to have association with thromboembolic events and have been found in hepatitis C virus (HCV) infection. Moreover, high prevalence of HCV infection and thrombotic risk is described in thalassemia. We aimed at investigating the prevalence of anticardiolipin antibodies (aCLAbs), lupus anticoagulant (LA), and their relation with HCV infection in Iranian thalassemic patients. Presence of anti-HCV antibody, serum HCV-RNA, aCLAbs, and LA activity was determined in 131 patients with thalassemia major (male/female: 63/68 aged 3-29 years) registered at thalassemia unit, Dastgheib Hospital, Shiraz, Iran. Sixty-one healthy controls were also included. Anti-HCV antibody was positive in 24 (18.3%), IgG aCLAbs in 56 (42.7%), and LA activity in 9 (6.9%) patients. 87.5% of patients positive for aCLAbs had a low titer of aCLAbs. Although none of the participants had a previous history of thrombosis, higher prevalence of aCLAbs was detected in thalassemic patients compared with controls. No significant difference in the prevalence of aCLAbs was found between HCV-infected and noninfected patients. A high prevalence of aCLAbs, the majority in low titers, was detected in Iranian thalassemic patients irrespective of previous history of thrombosis and presence of HCV infection.
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Affiliation(s)
- S Kashef
- Allergy Research Center, Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran.
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Abstract
PURPOSE OF REVIEW To review the current literature and summarize the main principles found between viral infections and the subsequent production of autoantibodies. RECENT FINDINGS We concentrate on recent findings involving three viral agents, one of which is Epstein-Barr virus, which has been associated with many autoimmune diseases and is classically considered to induce systemic lupus erythematosus. As we will discuss, this occurs through molecular mimicry between Epstein-Barr virus nuclear antigen 1 and lupus-specific antigens such as Ro, La or dsDNA, through induction of Toll-like receptor hypersensitivity by Epstein-Barr virus latent membrane protein 2A or by creating immortal B and T cells by loss of apoptosis. Hepatitis B virus was found to share amino acid sequences with different autoantigens. Tissue damage and the release of intracellular components is just another example of the autoantibody production caused by this virus. Cytomegalovirus has often been controversially associated with several autoimmune diseases and, although is the least understood viral infection of the three, appears to be somewhat suspicious. SUMMARY Understanding the infectious origin of autoimmune diseases is important as we aim to identify high-risk patients and disrupt this process with vaccines or other medications, ultimately delaying or even preventing the evolution of autoimmune diseases.
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Sène D, Piette JC, Cacoub P. Antiphospholipid antibodies, antiphospholipid syndrome and infections. Autoimmun Rev 2007; 7:272-7. [PMID: 18295729 DOI: 10.1016/j.autrev.2007.10.001] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2007] [Accepted: 10/01/2007] [Indexed: 12/13/2022]
Abstract
Since the association between antiphospholipid antibodies (aPL) and syphilis was first described, many other viral, bacterial and parasitic infections have been shown to induce antiphospholipid antibodies, notably anticardiolipin antibodies (aCL). A review of the literature shows that while aCL occur frequently in viral infections, particularly in HIV (49.75%), HBV (24%) and HCV (20%), it is very rarely associated with anti-beta2 glycoprotein I antibodies (anti-beta2GPI) and is not correlated with thrombosis risk or hematological manifestations of the antiphospholipid syndrome (APS). Concerning bacterial infections, aCL is often present in leprosy (42.7%), where it is frequently associated with the presence of anti-beta2GPI (44.8%), and in syphilis infections (8 to 67%), though without correlation with thrombotic events. Though few individual patients with unequivocal infection-induced aPL satisfy criteria for APS, the lack of statistical association with thrombotic events strongly argues against the identification of a true APS subset in this context. However, physicians should keep in mind the fact that an infection, generally bacterial, in patients with confirmed APS, may lead to catastrophic antiphospholipid syndrome with a possible fatal outcome.
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Affiliation(s)
- Damien Sène
- Université Pierre et Marie Curie-Paris 6, CNRS, UMR 7087, Paris, F-75013 France
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Federico A, Filippelli A, Falciani M, Tuccillo C, Tiso A, Floreani A, Naccarato R, Rossi F, Del Vecchio Blanco C, Loguercio C. Platelet aggregation is affected by nitrosothiols in patients with chronic hepatitis: In vivo and in vitro studies. World J Gastroenterol 2007; 13:3677-83. [PMID: 17659726 PMCID: PMC4250638 DOI: 10.3748/wjg.v13.i27.3677] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [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 relationship among the number of platelets and plasma levels of S-nitrosothiols (S-NO), nitrite, total non-protein SH (NPSH), glutathione (GSH), cysteine (CYS), malondialdehyde (MDA), 4-hydroxininenal (4HNE), tumor necrosis factor-alpha (TNFα) and interleukin (IL)-6 in patients with chronic hepatitis C (CH).
METHODS: In vitro the aggregation of platelets derived from controls and CH patients was evaluated before and after the addition of adenosine diphosphate (ADP) and collagen, both in basal conditions and after incubation with nitrosoglutathione (GSNO).
RESULTS: In vivo, S-NO plasma levels increased significantly in CH patients and they were significantly directly correlated with platelet numbers. Patients with platelet counts < 150 000/μL, had a smaller increase in S-NO, lower levels of GSH, CYS, NPSH, TNFα, and IL-6, and higher levels of nitrite, MDA, and 4-HNE relative to those of patients with platelet counts > 150 000/μL. In vitro, the ADP and collagen aggregation time was increased in platelets from patients and not from controls; in addition, platelets from CH patients but not from controls also showed a latency time after exposure to collagen.
CONCLUSION: The incubation of platelets with GSNO improved the percentage aggregation and abolished the latency time.
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Affiliation(s)
- A Federico
- Inter-University Research Centre on Foods, Nutrition and Gastrointestinal Tract, Gastroenterology School, 2nd University of Naples, Via Alcide De Gasperi 80, 84018 Scafati, Italy.
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Abstract
An association between infections and antiphospholipid antibodies (aPL) has been reported in several epidemiologic and experimental studies. Infection-induced aPL have been traditionally regarded as transient and were generally not associated with clinical features of antiphospholipid syndrome. The distinction between autoimmune and postinfectious aPL on the basis of requirement of binding cofactor is not absolute, and in recent years, several reports demonstrated that some patients can produce pathogenic antibodies in response to infection. Infections most frequently associated with antiphospholipid syndrome include parvovirus B19, cytomegalovirus, varicella-zoster virus, HIV, streptococcal and staphylococcal infections, gram-negative bacteria, and Mycoplasma pneumoniae.
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Affiliation(s)
- Tadej Avcin
- Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center Ljubljana, Vrazov trg 1, SI-1525 Ljubljana, Slovenia.
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Papamichalis PA, Zachou K, Koukoulis GK, Veloni A, Karacosta EG, Kypri L, Mamaloudis I, Gabeta S, Rigopoulou EI, Lohse AW, Dalekos GN. The revised international autoimmune hepatitis score in chronic liver diseases including autoimmune hepatitis/overlap syndromes and autoimmune hepatitis with concurrent other liver disorders. JOURNAL OF AUTOIMMUNE DISEASES 2007; 4:3. [PMID: 17603886 PMCID: PMC1933536 DOI: 10.1186/1740-2557-4-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2007] [Accepted: 06/29/2007] [Indexed: 02/08/2023]
Abstract
BACKGROUND We conducted a study in order to determine the usefulness and diagnostic value of International Autoimmune Hepatitis Group (IAHG) score in non-autoimmune hepatitis (AIH) hepatic disorders as well as in AIH/overlap syndromes and in cases with coexistence of AIH and other liver diseases. METHODS We applied the IAHG score in 423 patients with liver diseases excluding patients with AIH, AIH/overlap syndromes and AIH with concurrent other liver disease namely, patients with chronic hepatitis B (n = 109), chronic hepatitis C (n = 95), chronic hepatitis D (n = 4), alchoholic liver disease (n = 28), non-alcoholic fatty liver disease (n = 55), autoimmune cholestatic liver diseases (n = 77), liver disorders of undefined origin (n = 32) and with miscellaneous hepatic disorders (n = 23). 24 patients with AIH associated with any kind of liver disorder including 10 patients with AIH/overlap syndromes and 14 AIH with concurrent other liver disease were also investigated. 43 patients with AIH consisted the control group. RESULTS The specificity of the score was 98.1% while the sensitivity in unmasking AIH in patients with either AIH/overlap syndromes or AIH with concurrent other liver diseases was only 50% and 78.6%. In the binary logistic regression model, the presence of other autoimmune diseases (p < 0.001), the total histological score (p < 0.001) and positivity for autoantibodies (p < 0.05) were identified as independent predictors for the presnce of AIH/ovea syndromes o AI with concurren other liver diseass. CONCLUSION The IAHG scoring system has very good specificity for excluding AIH in patients with chronic liver diseases but not that sensitivity in order to unmask AIH/overlap syndromes or AIH with concurrent other liver diseases. The presence of other autoimmune diseases or autoantibody markers in the absence of hepatitis viral markers should alarm physicians for the possible presence of AIH either as "pure" AIH or in association with other liver disorders (AIH/overlap syndromes or AIH with concurrent other liver diseases). Under these conditions, liver histology seems essential and it must always be included in the work up of hepatic patients.
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Affiliation(s)
- Panagiotis A Papamichalis
- Dept of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Kalliopi Zachou
- Dept of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - George K Koukoulis
- Dept. of Pathology, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Aikaterini Veloni
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Efthimia G Karacosta
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Lampros Kypri
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Ioannis Mamaloudis
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Stella Gabeta
- Dept of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Eirini I Rigopoulou
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
| | - Ansgar W Lohse
- Dept. of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - George N Dalekos
- Dept of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
- Dept. of Medicine, Academic Liver Unit, Medical School, University of Thessaly, 22 Papakiriazi str, Larissa 41222, Greece
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Rigopoulou EI, Dalekos G, Bogdanos DP. How common are connective tissue disorders in patients with autoimmune hepatitis? Semin Arthritis Rheum 2007; 36:332; author reply 333. [PMID: 17276497 DOI: 10.1016/j.semarthrit.2006.11.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2006] [Accepted: 11/21/2006] [Indexed: 12/16/2022]
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Rigopoulou EI, Mytilinaiou M, Romanidou O, Liaskos C, Dalekos GN. Autoimmune hepatitis-specific antibodies against soluble liver antigen and liver cytosol type 1 in patients with chronic viral hepatitis. JOURNAL OF AUTOIMMUNE DISEASES 2007; 4:2. [PMID: 17274827 PMCID: PMC1796878 DOI: 10.1186/1740-2557-4-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Accepted: 02/04/2007] [Indexed: 02/08/2023]
Abstract
BACKGROUND Non-organ specific autoantibodies are highly prevalent in patients with chronic hepatitis C (HCV). Among them, anti-liver kidney microsomal type 1 (LKM1) antibody--the serological marker of type 2 autoimmune hepatitis (AIH-2)--is detected in up to 11% of the HCV-infected subjects. On the other hand, anti-liver cytosol type 1 antibodies (anti-LC1)--either in association with anti-LKM1, or in isolation--and anti-soluble liver antigen antibodies (anti-SLA) have been considered as useful and specific diagnostic markers for AIH. However, their specificity for AIH has been questioned by some recent studies, which have shown the detection of anti-LC1 and anti-SLA by immunoprecipitation assays in HCV patients irrespective of their anti-LKM1 status. The aim of the present study was to test the anti-LC1 and anti-SLA presence by specific enzyme linked immunosorbent assays (ELISAs), in a large group of Greek HCV-infected patients with or without anti-LKM1 reactivity as firstly, immunoprecipitation assays are limited to few specialized laboratories worldwide and cannot be used routinely and secondly, to assess whether application of such tests has any relevance in the context of patients with viral hepatitis since antibody detection based on such ELISAs has not been described in detail in large groups of HCV patients. METHODS One hundred and thirty eight consecutive HCV patients (120 anti-LKM1 negative and 18 anti-LKM1 positive) were investigated for the presence of anti-LC1 and anti-SLA by commercial ELISAs. A similar number (120) of chronic hepatitis B virus (HBV) infected patients seronegative for anti-LKM1 was also tested as pathological controls. RESULTS Six out of 18 (33%) anti-LKM(pos)/HCV(pos) patients tested positive for anti-LC1 compared to 1/120 (0.83%) anti-LKM(neg)/HCV(pos) patients and 0/120 (0%) of the anti-LKM1(neg)/HBV(pos) patients (p < 0.001 for both comparisons). Anti-SLA antibodies were not present in any of the HCV (with or without anti-LKM1) or HBV-infected patients. CONCLUSION We showed that anti-LC1 and anti-SLA autoantibodies are not detected by conventional assays in a large group of anti-LKM1 negative patients with chronic hepatitis B and C infections. Based on these results we cannot find any justification for the application of anti-LC1 and anti-SLA tests in the routine laboratory testing of viral hepatitis-related autoantibody serology with the only potential exception being the anti-LC1 screening in anti-LKM1(pos)/HCV(pos) patients.
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Affiliation(s)
- Eirini I Rigopoulou
- Department of Medicine, Academic Liver Unit and Research Laboratory of Internal Medicine, Larissa Medical School, University of Thessaly, Larissa, Greece
| | - Maria Mytilinaiou
- Department of Medicine, Academic Liver Unit and Research Laboratory of Internal Medicine, Larissa Medical School, University of Thessaly, Larissa, Greece
| | - Ourania Romanidou
- Department of Medicine, Academic Liver Unit and Research Laboratory of Internal Medicine, Larissa Medical School, University of Thessaly, Larissa, Greece
| | - Christos Liaskos
- Department of Medicine, Academic Liver Unit and Research Laboratory of Internal Medicine, Larissa Medical School, University of Thessaly, Larissa, Greece
- Institute of Biomedical Technology (BIOMED), Center for Research and Technology-Thessaly (CE.RE.TE.TH), Larissa, Greece
| | - George N Dalekos
- Department of Medicine, Academic Liver Unit and Research Laboratory of Internal Medicine, Larissa Medical School, University of Thessaly, Larissa, Greece
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Gatselis NK, Rigopoulou E, Stefos A, Kardasi M, Dalekos GN. Risk factors associated with HCV infection in semi-rural areas of central Greece. Eur J Intern Med 2007; 18:48-55. [PMID: 17223043 DOI: 10.1016/j.ejim.2006.09.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2006] [Revised: 07/20/2006] [Accepted: 09/19/2006] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) appears to be endemic in most parts of the world, but there is considerable geographic variation. In order to assess the geographic distribution of HCV in Thessaly, in central Greece, we conducted a retrospective study in HCV-infected patients attending the Academic Liver Unit of Thessaly University from 1999 to 2003. We also investigated whether variation among regions could be attributed to differences in risk factors. METHODS We evaluated the records of 309 HCV patients whose origin and/or residence was in Thessaly. To identify risk factors that were independently associated with the place of birth and/or residence, adjusted odds ratios (OR) were calculated by logistic regression analysis. We also studied the medical records of 150 HCV-negative patients from the same areas in order to evaluate whether there are differences in risk factors reported by HCV-positive and HCV-negative patients. RESULTS We found three municipalities with a high HCV frequency. The use of non-disposable, multiple-use glass syringes for medical purposes in the past was the only potential risk factor more frequently identified in these areas than in other places (OR=2.3; p<0.05). This risk factor was significantly (p<0.001) associated with older age of the infected patients. CONCLUSIONS This study shows that the spread of HCV in the three regions may have occurred several years ago as a result of the use of multiple-use glass syringes. Differences in prevalence rates among different age groups, as well as among different areas, indicate the need for extensive studies to determine HCV epidemiology and to develop appropriate prevention programs.
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Affiliation(s)
- Nikolaos K Gatselis
- Department of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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Lee CH, Wang IK, Chen TC, Chang HW, Yang CC, Chien YS, Wu CS, Chiou TTY, Wu MS, Wang PH, Chuang FR. Anticardiolipin antibodies and vascular access thrombosis in Taiwanese haemodialysis patients with chronic hepatitis C: a retrospective study. Int J Clin Pract 2006; 60:1591-5. [PMID: 16704678 DOI: 10.1111/j.1742-1241.2006.00857.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Hepatitis C virus causes various extrahepatic immunologic abnormalities. Vascular access thrombosis (VAT) is a major cause of morbidity in chronic haemodialysis (HD) patients. Immunoglobulin-G anticardiolipin antibody (IgG-ACA) is strongly associated with venous and arterial thrombosis in patients with normal renal function. Previous investigations have reported the association of raised IgG-ACA titre recurrent with VAT in HD patient, and also few equivalent studies were reported the same in Taiwan. This study attempted to determine whether raised IgG-ACA titres are associated with increased risk of recurrent VAT in HD patients with chronic hepatitis C. This study enrolled 98 chronic hepatitis C patients undergoing HD. IgG-ACA titre and hepatitis C marker were measured for all subjects. Raised IgG-ACA titres were present in 29.6% (29/98) of patients. In both groups (raised and normal IgG-ACA), the type of shunt did not differ (p = 0.416). There was strong association between raised IgG-ACA titre and recurrent VAT (p = 0.0004). In predicting for more or one episodes of VAT using multiple logistic regression, synthetic graft (p < 0.0001), raised IgG-ACA titre (p = 0.039), presence of hepatitis B (p = 0.004) and haemodialysis duration (p = 0.039) were significant factors. The prevalence of raised IgG-ACA titres was 39.6% among chronic hepatitis C with HD patients. There was strong association between raised IgG-ACA titre and recurrent VAT, and this finding may be the consequence of pathogenetic role of raised IgG-ACA titres on the development of VAT status in HD patients with chronic hepatitis C.
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Affiliation(s)
- C-H Lee
- Division of Nephrology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan
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Gatselis NK, Georgiadou SP, Koukoulis GK, Tassopoulos N, Zachou K, Liaskos C, Hatzakis A, Dalekos GN. Clinical significance of organ- and non-organ-specific autoantibodies on the response to anti-viral treatment of patients with chronic hepatitis C. Aliment Pharmacol Ther 2006; 24:1563-73. [PMID: 17094775 DOI: 10.1111/j.1365-2036.2006.03165.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Development of organ- and non-organ-specific autoantibodies has been reported in hepatitis C virus patients treated with interferon-alpha plus/minus ribavirin. AIMS To address whether prevalence and the titre of gastric parietal autoantibodies and non-organ-specific autoantibody in hepatitis C virus-treated patients were affected by therapy, and if the development of these antibodies carries any clinical significance on the response to treatment, as few studies in adults have been strictly designed to address the above hypothesis. METHODS Samples at three time-points (baseline, end of treatment, end of follow-up) from 102 hepatitis C virus patients (39 sustained responders, 26 relapsers, 33 non-responders; four lost in follow-up) were studied for gastric parietal autoantibodies and/or non-organ-specific autoantibody by indirect immunofluorescence, commercial and in-house enzyme-linked immunosorbent assays. RESULTS Sustained virological and biochemical response was associated with antinuclear antibody absence (end of treatment or end of follow-up), decrease of smooth-muscle antibody titres during therapy and gastric parietal autoantibodies negativity at baseline. However, after multivariate analysis only antinuclear antibody positivity at the end of treatment and increase of smooth-muscle antibody titres were associated with worst treatment response, independently of known factors of worst treatment outcome. CONCLUSIONS We were able to demonstrate a negative correlation between the efficacy of anti-viral treatment for hepatitis C virus and the presence of antinuclear antibody and smooth-muscle antibody before treatment, or their increase during therapy.
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Affiliation(s)
- N K Gatselis
- Department of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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Toubi E, Gordon S, Kessel A, Rosner I, Rozenbaum M, Shoenfeld Y, Zuckerman E. Elevated serum B-Lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity. J Autoimmun 2006; 27:134-9. [PMID: 17029886 DOI: 10.1016/j.jaut.2006.07.005] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2006] [Revised: 07/20/2006] [Accepted: 07/20/2006] [Indexed: 02/06/2023]
Abstract
In this study we aimed to determine whether serum B-lymphocyte activating factor (BAFF) level is increased in patients with chronic hepatitis C virus (HCV) infection, and to assess its association with HCV-related autoimmunity. Sixty-five patients with chronic HCV infection were compared with two disease control groups [57 patients with systemic lupus erythematosus (SLE) and 15 with chronic hepatitis B virus (HBV) infection] and a healthy control group of 35 individuals. A special attention was given to HCV-related arthralgia and or vasculitis. Serum BAFF was assessed in all studied individuals, whereas rheumatoid factor (RF), anti-cardiolipin antibodies (aCL), and cryoglobulins were determined in HCV and HBV infected patients, and anti-dsDNA antibodies and aCL were assessed in patients with SLE. Mean serum BAFF was increased in patients with HCV infection and SLE (2.4+/-0.8 ng/ml and 3.1+/-1.34 ng/ml respectively) compared to 1.1+/-0.14 ng/ml in patients with HBV; and to 1.1+/-0.27 in healthy controls (all, p<0.0001). The elevation in serum BAFF was associated with HCV-related arthralgia and or vasculitis (p<0.0001), and with the presence of aCL and of cryoglobulins. HBV patients lacked features suggestive of autoimmunity. In SLE patients, elevated serum BAFF was in association with the presence of anti-dsDNA (p=0.002). As in other autoimmune diseases, increased serum BAFF was also found in patients with chronic HCV infection. Elevated serum BAFF levels were associated with clinical and laboratory features of autoimmunity, suggesting that BAFF may play a role in HCV-related autoimmunity.
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Affiliation(s)
- E Toubi
- Division of Clinical Immunology and Allergy, Bnai-Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
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Zachou K, Liaskos C, Rigopoulou E, Gabeta S, Papamichalis P, Gatselis N, Georgiadou S, Dalekos GN. Presence of high avidity anticardiolipin antibodies in patients with autoimmune cholestatic liver diseases. Clin Immunol 2006; 119:203-212. [PMID: 16500150 DOI: 10.1016/j.clim.2006.01.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2005] [Revised: 01/11/2006] [Accepted: 01/14/2006] [Indexed: 01/04/2023]
Abstract
We studied the prevalence and clinical significance of anticardiolipin antibodies (aCL) in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) as similar data are missing. Ninety-nine PBC patients, 41 PSC, 228 HCV, 50 HBV, 111 with other non-viral and non-autoimmune liver disorders and 267 healthy were investigated. In order to evaluate the avidity of aCL, urea 2 M was used. IgG and/or IgM aCL were detected in 40% of PBC and PSC patients, in 26.2% of disease controls (P < 0.05) and 2.25% of healthy (P < 0.05). In PBC, IgG aCL associated with presence of cirrhosis, increased Mayo risk score and thrombocytopenia, while in PSC with longer disease duration and biochemical activity. Anti-beta2-GPI was detected in only three patients. Both in PBC and PSC, resistance of aCL to urea was high, similar to that observed in antiphospholipid syndrome (APS). We demonstrated a significantly higher prevalence of aCL in PBC and PSC compared to other liver diseases and healthy. aCL were associated with more severe disease in PBC and biochemical activity in PSC, but they rather seem to be "non-pathogenic" (co-factor-independent). However, their avidity was comparable with that of APS, indicating the need for prospective studies in order to address whether aCL in PBC and PSC may contribute to APS development or the progression of hepatic disease.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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Zografos TA, Rigopoulou EI, Liaskos C, Togousidis E, Zachou K, Gatselis N, Germenis A, Dalekos GN. Alterations of leptin during IFN-alpha therapy in patients with chronic viral hepatitis. J Hepatol 2006; 44:848-55. [PMID: 16530290 DOI: 10.1016/j.jhep.2006.01.025] [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] [Received: 08/30/2005] [Revised: 12/19/2005] [Accepted: 01/04/2006] [Indexed: 01/04/2023]
Abstract
BACKGROUND/AIMS Leptin has a particular profibrogenic role in the liver. We investigated whether IFN-alpha influences leptin production in patients with chronic hepatitis B (CHB) and C (CHC). Leptin was determined in serial samples from 63 CHB and 42 CHC IFN-alpha treated patients. Furthermore, we evaluated whether leptin alterations were associated with patients' characteristics. METHODS Sera were investigated at serial time-points using an enzyme-linked-immunosorbent-assay. Controls consisted of 36 patients with autoimmune liver diseases and 44 healthy patients. RESULTS Leptin levels before IFN-alpha administration were higher in CHB and CHC compared to healthy (P<0.004) and diseased controls (P=0.0001). In CHB patients, we observed a significant reduction of leptin during IFN-alpha treatment and lasting for up to 6 months after the end of treatment, followed by an increase reaching pretreatment levels at 1.5 years after stopping therapy. The pattern of leptin alterations was similar in CHC patients where leptin's decrease was more pronounced at 6 months after the end of treatment. Biochemical or virological response to treatment was not associated with leptin reduction in both groups. CONCLUSIONS This study provides information on leptin kinetics during IFN-alpha treatment and follow-up in CHB and CHC patients and suggests IFN-alpha as a potential inhibitor of leptin production.
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Affiliation(s)
- Theodoros A Zografos
- Research Laboratory of Internal Medicine, Department of Medicine, Medical School, University of Thessaly, 41222 Larissa, Greece
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Chuang FR, Chang HW, Lin CL, Wang IK, Chang HY, Wang PH, Yang CC, Chen TC, Wu CS, Lee CH. Anticardiolipin antibody and Taiwanese chronic haemodialysis patients with recurrent vascular access thrombosis. Int J Clin Pract 2005; 59:785-90. [PMID: 15963205 DOI: 10.1111/j.1742-1241.2005.00493.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Vascular access failure is a major cause of morbidity in chronic haemodialysis (HD) patients. However, some factors (such as homocysteine levels) are known regarding the risk factors predisposing certain HD patients to vascular access thrombosis (VAT). Immunoglobulin-G anticardiolipin antibody (IgG-ACA) is strongly associated with venous and arterial thrombosis in patients with normal renal function. Previous investigations have reported the characteristics of patients with raised IgG-ACA titre and recurrent VAT of HD in Western countries, but few equivalent studies exist for Taiwan. This retrospective study attempts to determine whether raised IgG-ACA titres are associated with an increased risk of recurrent VAT in chronic HD patients. This study enrolled 483 patients undergoing HD. IgG-ACA titre and hepatitis B&C marker were measured for all patients. A history of recurrent (VAT more than one) and/or VAT was elicited by using information from the patient questionnaires and was verified by means of careful inpatient and outpatient chart review. Raised IgG-ACA titres were present in 21.7% (105/483) of patients. In both groups (raised IgG-ACA and normal IgG-ACA), the type of shunt differed significantly (p = 0.029). In predicting for more or one episodes of VAT by using multiple logistic regression with all significant factors, synthetic graft was also a significant factor (p < 0.0001). The 105 raised IgG-ACA titres and 378 normal IgG-ACA titres were associated between chronic HD patients and recurrent VAT (p = 0.034). In predicting for more or one episode of VAT by using multiple logistic regression with all significant factors, raised IgG-ACA titre was a non-significant factor (p = 0.336). The presence of hepatitis C had a higher percentage in group with raised IgG-ACA titres of HD patients (p = 0.042). In predicting for more or one episode of VAT by using multiple logistic regression with all significant factors, the presence of hepatitis C was also a significant factor (p = 0.022). In conclusion, the prevalence of raised IgG-ACA titres was 21.7% among HD patients. There was a weak association between raised IgG-ACA titre and recurrent VAT and this finding may be the consequence of pathogenetic role of raised IgG-ACA titres in the development of VAT status for chronic HD patients. The presence of hepatitis C was a cofactor.
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Affiliation(s)
- F-R Chuang
- Division of Nephrology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan
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Alvarez Suero J, Moyano Franco MJ, Serrano Carrillo JL, Venero Gómez J. [Antiphospholipid antibodies induced by Chlamydia pneumoniae infections]. Med Clin (Barc) 2005; 124:519. [PMID: 15847779 DOI: 10.1157/13073572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Palazzi C, Olivieri I, Cacciatore P, Pennese E, D'Amico E. Management of hepatitis C virus-related arthritis. Expert Opin Pharmacother 2005; 6:27-34. [PMID: 15709880 DOI: 10.1517/14656566.6.1.27] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In recent years, hepatitis C virus-related arthritis (HCVrA) has been recognised as an autonomous rheumatic disorder. Two subsets of the disease have been identified: a polyarthritis involving small joints that resembles rheumatoid arthritis, but is usually milder, and a mono-oligoarthritis that shows an intermittent course and is frequently associated with the presence of cryo-globulins in serum. Few data about HCVrA treatment are reported in the literature. As a consequence, the therapeutic approach for this disorder is still largely empirical. Hydroxychloroquine, low doses of corticosteroids and NSAIDs are frequently administered to patients with HCVrA, but some authors describe an incomplete relief of symptoms, especially in the rheumatoid-like subset. Intake of low doses of corticosteroids and NSAIDs is more effective in subjects belonging to the mono-oligoarthritis group. Use of antiviral drugs (IFN plus ribavirin) shows good results, but IFN can induce or worsen autoimmune disorders. For this reason, in our opinion, this approach should be prescribed only when required by the coexistent liver disease. On the basis of the poor available data, the administration of anti-TNF-alpha agents seems safe in HCV patients, but the usually non-aggressive course of HCVrA does not justify their use as a current therapy.
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Affiliation(s)
- Carlo Palazzi
- Villa Pini Clinic, Division of Rheumatology, Via dei Frentani, 228, 66100 Chieti, Italy.
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Gatselis NK, Georgiadou SP, Tassopoulos N, Zachou K, Liaskos C, Hatzakis A, Dalekos GN. Impact of parietal cell autoantibodies and non-organ-specific autoantibodies on the treatment outcome of patients with hepatitis C virus infection: A pilot study. World J Gastroenterol 2005; 11:482-7. [PMID: 15641130 PMCID: PMC4250795 DOI: 10.3748/wjg.v11.i4.482] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Various side effects have been reported in patients infected with hepatitis C virus (HCV) who were treated with interferon-alpha (IFN-α), including the appearance or exacerbation of underlying autoimmune diseases and the development of a variety of organ and non-organ specific autoantibodies (NOSA). However, very few studies in adults have been strictly designed to address: whether the prevalence and the titre of organ and NOSA in serial samples of HCV-treated patients were affected by IFN-α, and the impact of these autoantibodies on the treatment outcome of HCV patients.
METHODS: We investigated whether parietal cell autoantibodies (PCA) and/or NOSA were related with treatment-outcome in 57 HCV-treated patients (19 sustained-responders, 16 relapsers, 22 non-responders). Serum samples from patients were studied blindly at three time-points (entry, end of treatment and end of followup). For the detection of autoantibodies we used indirect immunofluorescence, commercial and in-house ELISAs.
RESULTS: Sustained biochemical response was associated with ANA-negativity at the entry or end of follow up. Sustained virological response was associated with the absence of PCA at the entry. Combined virological and biochemical sustained response (CVBSR) was associated with the absence of antinuclear antibodies (ANA) at the end of follow up and PCA-negativity at the entry. Sustained virological and CVBSR were associated with a reduction of ANA and SMA titers during therapy.
CONCLUSION: Although PCA and/or NOSA seropositivity should not affect the decision to treat HCV patients, the presence of some of them such as ANA, PCA and SMA before treatment or their increase during therapy with IFN- α may predict a worse response, indicating the need for a closer monitoring during treatment of HCV patients positive for these autoantibodies.
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Affiliation(s)
- Nikolaos K Gatselis
- Department of Internal Medicine, Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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Abstract
The hepatitis C virus (HCV) infection is a worldwide disease that is characterized by a preferential chronic evolution with mild to severe liver disease, including cirrhosis and, in lesser proportion, hepatocarcinoma. Out of these complications, HCV is frequently reported to complicate extrahepatic manifestations. Among those associated to HCV infection with a high degree of certainty, mixed cryoglobulinemia and its complications (skin, neurological, renal, rheumatological involvement) are the most prevalent (50%) in HCV-infected patients. The other diseases include noncryoglobulinemic systemic vasculitis, splenic lymphoma with villous lymphocytes, fatigue, porphyria cutanea tarda, sicca syndrome, and autoantibodies production. The extrahepatic manifestations that share mild-degree certainty of association with HCV infection include B-cell non-Hodgkin lymphoma, autoimmune thrombocytopenia, pruritus, and type II diabetes mellitus. The other diseases such as autoimmune thyroiditis, lichen planus are more questionable for their eventual association with HCV and others (pulmonary fibrosis with or without polymyositis, progressive encephalomyelitis, Mooren's corneal ulcers, erythema nodosum, chronic polyradiculonevritis) are mostly case reports. Howerver, even in cases of tight association, the mechanisms through which HCV may promote or induce extrahepatic manifestations remain unclear and merit further investigations.
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Affiliation(s)
- Damien Sène
- Department of Internal Medicine, Boulevard de l'hôpital, Paris, France
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Georgiadou SP, Zachou K, Rigopoulou E, Liaskos C, Mina P, Gerovasilis F, Makri E, Dalekos GN. Occult hepatitis B virus infection in Greek patients with chronic hepatitis C and in patients with diverse nonviral hepatic diseases. J Viral Hepat 2004; 11:358-65. [PMID: 15230859 DOI: 10.1111/j.1365-2893.2004.00513.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Occult hepatitis B virus (HBV) infection has been reported in patients with chronic hepatitis C who are negative for HBV surface antigen (HBsAg). However, the significance of 'silent' HBV in hepatitis C virus (HCV) infection is unknown. We investigated 540 subjects for the presence of occult HBV in Greek HCV patients, patients with nonviral liver diseases and healthy donors in an attempt to determine the frequency and importance of this phenomenon. One hundred and eighty-seven anti-HCV(+)/HBsAg(-) patients' sera were investigated for the presence of HBV-DNA by polymerase chain reaction. Two hundred and eighty-two selected blood donors (positive for antibodies to HBV core antigen) and 71 patients with various nonviral hepatic diseases consisted the control groups [both controls were anti-HCV(-)/HBsAg(-)]. HBV-DNA was detected in 26.2% of HCV-infected patients vs 8.5% of patients with nonviral diseases (P = 0.003) and 0/282 of donors (P = 0.0000). HBV-DNA was neither associated with HBV markers, nor with the clinical status of HCV and nonHCV patients. Neither epidemiological, histologic and virologic data nor the response to therapy were associated with the HBV-DNA detection. Hence one quarter of HCV-infected patients had occult HBV infection. Similar findings were not found in both control groups. Occult HBV infection in Greek patients with chronic hepatitis C does not seem to modify the progression of chronic liver disease. Further studies of longer duration are needed in order to clarify the role of 'silent' HBV infection in HCV-infected patients.
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Affiliation(s)
- S P Georgiadou
- Research Laboratory of Internal Medicine, Medical School, University of Thessaly Larissa, Thessaly, Greece
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