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1
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Benedini L. Advanced protein drugs and formulations. Curr Protein Pept Sci 2021; 23:2-5. [PMID: 34895120 DOI: 10.2174/1389203722666211210115040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/03/2021] [Accepted: 11/06/2021] [Indexed: 11/22/2022]
Abstract
For a long time, proteins were a subset of molecules rarely applied as therapeutically active molecules. Some of the first applications of proteins as drugs have been insulin and vaccines for supply a physiological deficiency and the prevention of diseases, respectively. Nowadays, proteins have increased their range of application, not only as drugs but also as drug delivery systems to be administered by different routes. Due to their nature, proteins show different behavior while the conditions of the environment are modified. For this reason, it has been necessary to study their behavior for predicting the correct manufacturing, storing, or combination with other possible molecules in a formulation or into the body. The application of techniques for predicting the behavior of proteins in different environments has led to associate this type of behavior into the body with the occurrence of diseases such as celiac disease or Alzheimer's disease. Thus, this work shows an overview of the main types of proteins applied as active therapeutically molecules, proteins-based drug delivery systems, and techniques for predicting their stability into the storing container and the body.
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Affiliation(s)
- Luciano Benedini
- CONICET-INQUISUR, Universidad Nacional del Sur, Bahía Blanca 8000. Argentina
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2
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Rossi D, Sciascia S, Fenoglio R, Ferro M, Baldovino S, Kamgaing J, Ventrella F, Kalikatzaros I, Viziello L, Solfietti L, Barreca A, Roccatello D. Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy. Minerva Med 2020; 112:162-174. [PMID: 33198442 DOI: 10.23736/s0026-4806.20.07076-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cryoglobulinemia is defined by the presence of immunoglobulins having the following characteristics: forming a gel when temperature is <37 °C, precipitate in a reversible manner in the serum, and redissolve after rewarming. The presence of both polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type III) identifies the mixed cryoglobulinemia (MC). The identification of the Hepatitis C virus (HCV) infection in most of the cases previously defined as "essential" represented a cornerstone in the understanding the pathogenesis of this condition. The picture of MC comprehends heterogeneous clinical presentations: from arthralgias, mild palpable purpura, fatigue to severe vasculitis features with skin necrotic pattern, peripheral neuropathy and, less commonly, lungs, central nervous system, gastrointestinal tract, and heart involvement. The kidney represents the most common organ presentation, and the presence of glomerulonephritis is a key element when considering prognosis. We discuss the clinical presentation and histological features, diagnostic pitfalls, and controversies in the management of patients with cryoglobulinemic glomerulonephritis, with a special focus on reporting our experience in treating patients with B cell depletion therapy.
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Affiliation(s)
- Daniela Rossi
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Savino Sciascia
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Roberta Fenoglio
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Michela Ferro
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Simone Baldovino
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Joelle Kamgaing
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Federica Ventrella
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Ileana Kalikatzaros
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Lucia Viziello
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Laura Solfietti
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Antonella Barreca
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy.,Patology Division, A.O.U. Città della Salute e della Scienza, Turin, Italy
| | - Dario Roccatello
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy -
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3
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Kayali Z, Labrecque DR, Schmidt WN. Treatment of hepatitis C cryoglobulinemia: mission and challenges. ACTA ACUST UNITED AC 2012; 9:497-507. [PMID: 17081483 DOI: 10.1007/s11938-006-0006-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mixed cryoglobulinemia (MC) is a syndrome resulting from cold-insoluble immunoglobulin complexes or cryoglobulins (CGs) that precipitate in the serum of 40% to 50% of patients with chronic hepatitis C virus (HCV) infection. The pathogenesis of cryoglobulinemia likely occurs due to chronic viremia and generation of rheumatoid factor following continuous presentation of antigen-immunoglobulin complexes to B cells. CGs are thought to be responsible for a variety of extrahepatic manifestations associated with HCV, including vasculitis, glomerulonephritis, arthritis, and neuropathies, which occur in approximately 10% of HCV patients with CGs. CGs also are a powerful predictive factor for progressive liver disease and the aggressive reoccurrence of liver disease in HCV-positive patients after liver transplantation. First-line therapy for MC due to HCV infection is antiviral therapy with pegylated interferon-alpha and ribavirin. Viral eradication usually produces marked reduction of physical complications and arrests end organ damage concomitant with clearance of CG. Additional prospective, controlled studies are necessary to determine whether CG influences patient virologic response and/or its durability to antiviral therapy. Immunomodulators such as corticosteroids and cyclophosphamide are efficacious for palliative treatment of the symptomatology of HCV cryoglobulinemia but may enhance viral replication. Consequently, prolonged therapy with immunomodulatory agents should be limited to severe vasculitis or aggressive glomerulonephritis in patients with MC due to HCV who have failed to respond to antiviral therapy. In acute, fulminant presentations, plasmapheresis may provide temporary relief and arrest the rapid progression of the disease so that additional therapy can be initiated.
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Affiliation(s)
- Zeid Kayali
- Division of GI/Hepatology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 4553 JCP, Iowa City, IA 52242, USA.
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4
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Velasco A, Islam S, Nugent K. Bilateral foot necrosis caused by hepatitis C virus-induced mixed type II cryoglobulinemia. Clin Gastroenterol Hepatol 2011; 9:A22. [PMID: 21699801 DOI: 10.1016/j.cgh.2011.05.004] [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: 04/04/2011] [Revised: 04/28/2011] [Accepted: 05/03/2011] [Indexed: 02/07/2023]
Affiliation(s)
- Alejandro Velasco
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
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5
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Pietrogrande M, De Vita S, Zignego AL, Pioltelli P, Sansonno D, Sollima S, Atzeni F, Saccardo F, Quartuccio L, Bruno S, Bruno R, Campanini M, Candela M, Castelnovo L, Gabrielli A, Gaeta GB, Marson P, Mascia MT, Mazzaro C, Mazzotta F, Meroni P, Montecucco C, Ossi E, Piccinino F, Prati D, Puoti M, Riboldi P, Riva A, Roccatello D, Sagnelli E, Scaini P, Scarpato S, Sinico R, Taliani G, Tavoni A, Bonacci E, Renoldi P, Filippini D, Sarzi-Puttini P, Ferri C, Monti G, Galli M. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev 2011; 10:444-54. [PMID: 21303705 DOI: 10.1016/j.autrev.2011.01.008] [Citation(s) in RCA: 157] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 01/28/2011] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. METHODS Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. RESULTS An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. CONCLUSION Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.
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Affiliation(s)
- Maurizio Pietrogrande
- Medicina Interna, Department of Medicine, Surgery and Dentistry, Policlinico San Marco of Zingonia, University of Milan, Italy
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Vigani AG, Macedo de Oliveira A, Tozzo R, Pavan MHP, Gonçales ES, Fais V, Gonçales NS, Gonçales FL. The association of cryoglobulinaemia with sustained virological response in patients with chronic hepatitis C. J Viral Hepat 2011; 18:e91-8. [PMID: 20969676 DOI: 10.1111/j.1365-2893.2010.01385.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Previous reports suggest cryoglobulinemia might influence the hepatitis C virus (HCV) infection clinical course and treatment response but this association has not been thoroughly evaluated. We aimed to assess the relationship between cryoglobulinemia and sustained viral response (SVR) in patients treated for HCV infection. We included patients with HCV infection treated from January 2003 through December 2006. Biochemical analyses, detection cryoglobulinemia, and liver biopsies were performed prior to treatment. Genotype 1 or 4 infections received Peg-interferon (IFN) alpha-2a or -2b for 48 weeks; genotypes 2 or 3 received IFN alpha for 24 weeks. All patients also received ribavirin. Of 329 enrolled patients, 242 (73%) were male and the median age was 43 years. Cryoglobulinemia was detected in 196 (59.6%) patients; liver biopsy was performed in 301. Multivariate analysis showed an association of cryoglobulinemia with severe active necroinflammation (A3) (adjusted odds ratio [AOR] = 9.48; 95% confidence interval [CI]: 1.50-59.92) and rheumatoid factor (RF) level (AOR = 1.01; 95% CI: 1.00-1.02). Variables associated with advanced fibrosis were age, aspartate aminotransferase and alkaline phosphatase levels, alcohol use, and presence of diabetes. Variables independently associated with SVR were cryoglobulinemia (AOR = 2.33, 95% CI: 1.26-4.32), absence of cirrhosis (AOR = 4.5, 95% CI: 1.4-14.80), and RF level (AOR = 1.008, 95% CI: 1.001-1.014). Our findings suggest cryoglobulinemia is associated with severe necroinflammatory activity in HCV-infected patients. We also provide the first evidence for an association between cryoglobulinemia and higher SVR rates, highlighting its potential role as a prognostic factor for treatment response.
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Affiliation(s)
- A G Vigani
- Departamento de Clínica Médica, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo, Brazil.
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7
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Management of hepatitis C virus-related mixed cryoglobulinemia. Am J Med 2010; 123:400-8. [PMID: 20399313 DOI: 10.1016/j.amjmed.2009.09.038] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 09/09/2009] [Accepted: 09/10/2009] [Indexed: 01/14/2023]
Abstract
Mixed cryoglobulinemia is a chronic immune complex-mediated disease strongly associated with hepatitis C virus (HCV) infection. Mixed cryoglobulinemia is a vasculitis of small and medium-sized arteries and veins, due to the deposition of complexes of antigen, cryoglobulin and complement in the vessel walls. The main clinical features of mixed cryoglobulinemia vasculitis include the triad of palpable purpura, arthralgias, and weakness, and other pathological conditions such as glomerulonephritis, peripheral neuropathy, skin ulcers, and widespread vasculitis. The treatment of HCV-related mixed cryoglobulinemia is difficult due to the multifactorial origin and clinical polymorphism of the syndrome. It can be directed to eradicate the HCV infection, suppress the B-cell clonal expansion and cryoglobulin production, or ameliorate symptoms. The choice of the most appropriate treatment is strictly related to the assessment of disease activity, and to the extent and severity of organ involvement.
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8
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Parise ER, de Oliveira AC, Ferraz ML, Pereira AB, Leite KR. Cryoglobulinemia in chronic hepatitis C: clinical aspects and response to treatment with interferon alpha and ribavirin. Rev Inst Med Trop Sao Paulo 2007; 49:67-72. [PMID: 17505661 DOI: 10.1590/s0036-46652007000200001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2005] [Accepted: 09/06/2006] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION: The main extra-hepatic manifestation of hepatitis C is mixed cryoglobulinemia (MC). The aim of this study was to evaluate its prevalence among patients with chronic hepatitis C (CHC), to correlate its presence to host and virological variables and to the response to combined therapy with interferon-alpha and ribavirin. CASUISTIC AND METHODS: 202 CHC naive patients (136 with chronic hepatitis and 66 with cirrhosis) were consecutively evaluated for the presence of cryoglobulins. Cryoprecipitates were characterized by immunoelectrophoresis and classified according to the Brouet's criteria. RESULTS: The prevalence of MC was 27% (54/202), and 24% of them (13/54) showed major clinical manifestation of the disease. Even though type III MC was more frequent (78%), symptomatic MC was more common in type II MC. The presence of cirrhosis (RR = 2.073; IC95% = 1.029 - 4.179; p = 0.041), and age of the patients (RR = 1.035; IC95% = 1.008 - 1.062; p = 0.01) were independently associated with the presence of cryoglobulins. No relationship was found with viral load and genotype. 102 patients were treated with interferon alpha and ribavirin. Among these, 31 had MC. Sustained virological response (around 30%) was similar in patients with and without MC (p = 0.971). CONCLUSION: MC represents a prevalent complication in patients with CHC, specially older and cirrhotic patients. Only 24% of these patients show clinical manifestation of the disease, specially those with type II MC. The presence of MC did not affect the response to therapy.
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Affiliation(s)
- Edison Roberto Parise
- Disciplina de Gastrenterologia da Universidade Federal de São Paulo, and Anatomia Patológica, Hospital Sírio-Libanes, São Paulo, SP, Brazil.
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Berk DR, Mallory SB, Keeffe EB, Ahmed A. Dermatologic disorders associated with chronic hepatitis C: effect of interferon therapy. Clin Gastroenterol Hepatol 2007; 5:142-51. [PMID: 16919505 DOI: 10.1016/j.cgh.2006.06.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis C virus infection (HCV) is associated with extrahepatic manifestations, including such dermatologic conditions as mixed cryoglobulinemia, porphyria cutanea tarda, and lichen planus. Patients with chronic HCV and extrahepatic manifestations are often excluded from clinical trials evaluating interferon (IFN) therapy due to concerns about poor response, adverse events, and toxicity. Thus, data regarding the efficacy of IFN not only on the underlying chronic HCV, but also on extrahepatic manifestations, are limited in these patients. Case reports suggest that the response of dermatologic extrahepatic manifestations to IFN in patients with chronic HCV is highly variable. This review summarizes available data on dermatologic conditions associated with chronic HCV and their response to IFN therapy.
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Affiliation(s)
- David R Berk
- Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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10
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Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006; 130:231-64; quiz 214-7. [PMID: 16401486 DOI: 10.1053/j.gastro.2005.11.010] [Citation(s) in RCA: 267] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Jules L Dienstag
- Gastrointestinal Unit (Medical Services) Massachusetts General Hospital, Department of Medicine and Office of the Dean for Medical Education, Harvard Medical School, Boston, Massachusetts, USA
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11
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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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12
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Medina J, García-Buey L, Moreno-Otero R. Hepatitis C virus-related extra-hepatic disease--aetiopathogenesis and management. Aliment Pharmacol Ther 2004; 20:129-41. [PMID: 15233692 DOI: 10.1111/j.1365-2036.2004.01919.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Summary Hepatitis C virus infection is often associated with extra-hepatic manifestations, secondary to the elicitation of autoimmune reactions, generalized deposition of immune complexes and lymphoproliferative disorders. The most clearly established associations are those linking chronic hepatitis C with mixed cryoglobulinaemia (and the related glomerulonephritis and cutaneous vasculitis), as well as with the presence of autoantibodies. Less well-documented disorders include non-Hodgkin's lymphoma, thrombocytopenia, sialadenitis, thyroid disease, lichen planus, porphyria cutanea tarda, rheumatoid disorders and neurological disorders. Extra-hepatic manifestations are most frequent in patients of female sex, advanced age, long-lasting infection and cirrhosis. Optimal treatment strategies should be based on the predominant manifestation of the disease. In the case of autoimmune disorders not clearly attributable to the viral infection, corticosteroids may be the most effective option. Interferon-alpha alone or in combination with ribavirin may be indicated for those disorders related to immune complex deposition, such as mixed cryoglobulinaemia, although relapses of extra-hepatic signs often occur on discontinuation of treatment. In some cases, interferon-alpha may induce or exacerbate some extra-hepatic manifestations.
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Affiliation(s)
- J Medina
- Unidad de Hepatología, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain
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13
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Abstract
Hepatitis C is both a cause and a complication of chronic renal disease. Chronic infection with hepatitis C virus (HCV) can lead to the immune complex syndromes of cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN). The pathogenetic mechanisms for these conditions have not been defined, although they are clearly caused by the chronic viral infection. Management of HCV-related cryoglobulinemia and MPGN is difficult; antiviral therapy is effective in clearing HCV infection in a proportion of patients, but these conditions can be severe and resistant to antiviral therapy. Hepatitis C also is a complicating factor among patients with end-stage renal disease and renal transplants. The source of HCV infection in these patients can be nosocomial. Screening and careful attention to infection control precautions are mandatory for dialysis units to prevent the spread of hepatitis C. Prevention of spread is particularly important in these patients because HCV infection is associated with significant worsening of survival on dialysis therapy, as well as after kidney transplantation. Furthermore, therapy for hepatitis C is problematic, only partially effective, and associated with significant side effects in this population. There are significant needs in both basic and clinical research in the pathogenesis, natural history, prevention, and therapy for hepatitis C in patients with renal disease.
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Affiliation(s)
- Catherine M Meyers
- Division of Kidney, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, MD 20892, USA
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Wietzke-Braun P, Braun F, Schott P, Ramadori G. Is laparoscopy an advantage in the diagnosis of cirrhosis in chronic hepatitis C virus infection? World J Gastroenterol 2003; 9:745-50. [PMID: 12679924 PMCID: PMC4611442 DOI: 10.3748/wjg.v9.i4.745] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To evaluate the potential of laparoscopy in the diagnosis of cirrhosis and outcome of interferon treatment in HCV-infected patients.
METHODS: In this retrospective study, diagnostic laparoscopy with laparoscopic liver biopsy was performed in 72 consecutive patients with chronic HCV infection. The presence or absence of cirrhosis was analyzed macroscopically by laparoscopy and microscopically by liver biopsy specimens. Clinical and laboratory data and outcome of interferon-alfa treatment were compared between cirrhotic and noncirrhotic patients.
RESULTS: Laparoscopically, cirrhosis was seen in 29.2% (21/72) and non-cirrhosis in 70.8% (51/72) of patients. Cirrhotic patients were significantly older with a significant longer duration of HCV infection than noncirrhotic patients. Laboratory parameters (AST, y-GT, y-globulin fraction) were measured significantly higher as well as significantly lower (prothrombin index, platelet count) in cirrhotic patients than in non-cirrhotic patients. Histologically, cirrhosis was confirmed in 11.1% (8/72) and non cirrhosis in 88.9% (64/72). Patients with macroscopically confirmed cirrhosis (n = 21) showed histologically cirrhosis in 38.1% (8/21) and histologically non-cirrhosis in 61.9% (13/21). In contrast, patients with macroscopically non-cirrhosis (n = 51) showed histologically non cirrhosis in all cases (51/51). Thirty-nine of 72 patients were treated with interferon-alfa, resulting in 35.9% (14/39) patients with sustained response and 64.1% (25/39) with non response. Non-responders showed significantly more macroscopically cirrhosis than sustained responders. In contrast, there were no significant histological differences between non-responders and sustained responders.
CONCLUSION: Diagnostic laparoscopy is more accurate than liver biopsy in recognizing cirrhosis in patients with chronic HCV infection. Liver biopsy is the best way to assess inflammatory grade and fibrotic stage. The invasive marker for staging, prognosis and management, and treatment outcome of chronic HCV-infected patients need further research and clinical trials. Laparoscopy should be performed for recognition of cirrhosis if this parameter is found to be of prognostic and therapeutic relevance in patients with chronic HCV infection.
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Affiliation(s)
- Perdita Wietzke-Braun
- Medizinische Universitatsklinik, Abteilung Gastroenterologie, Robert-Koch-Strabetae 40, 37075 Goettingen, Germany
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15
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Abstract
Monoclonal antibody and recombinant DNA technologies have led to the development of biologic therapies capable of directly targeting selected components of the immune response. With the steady expansion of knowledge regarding the mechanisms of vascular inflammation, the safety and efficacy of biologic agents in the vasculitic diseases are being increasingly investigated. By targeting specific effector mechanisms involved in the pathogenesis of vasculitis, these agents may provide a less toxic means of inducing remission and lessening relapse. However, the study of biologic therapies in the vasculitides must be approached with caution, as unanticipated effects on disease activity and disease-specific toxicities can occur. Studies to examine these agents must recognize the potential for active vasculitis to be organ- or life-threatening as well as the current existence of effective therapies. In the research setting, investigation of biologic agents in the treatment of vasculitic diseases may also provide important insights into pathogenesis of these syndromes.
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Affiliation(s)
- Carol A Langford
- Immunologic Diseases Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
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16
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Abstract
Approximately 40% of patients with chronic hepatitis C virus (HCV) infection develop detectable serum cryoglobulins or cryoprecipitates (CP), although most do not show clinical or physical signs of syndromic cryoglobulinemia. Although association of HCV with the extrahepatic complications of cryoglobulinemia is widely recognized, the relationship of cryoglobulinemia with liver disease is unclear. We wished to study the relationship between CP and cirrhosis and to determine whether the development of CP is a true covariate for progressive liver disease or a confounding variable that impacts cirrhosis because of patient age, duration of disease, or differences in gender. We undertook a meta-analysis of 19 studies published between 1994 and 2001. The incidence of cirrhosis was compared in patients with and without CP after logistic regression adjustments for accepted risk factors for progressive liver disease, including age, gender, and estimated duration of disease (EDD). A total of 2,323 patients with chronic hepatitis C were identified, with 1,022 (44%) having detectable CP. Cirrhosis was present in 40% of patients with CP but only 17% of patients without CP (total Chi;(2) = 141.69, P <.001). After adjusting for age, gender, and estimated duration of disease by logistic regression, the combined odds ratio for incidence of cirrhosis in patients CP positive versus CP negative was 4.87, (95% CI: 3.32, 7.15), indicating a highly significant association between cirrhosis and cryoglobulinemia. In conclusion, cryoglobulins may be a useful prognostic indicator for increased risk of cirrhosis with chronic hepatitis C.
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Affiliation(s)
- Zeid Kayali
- Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, USA
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De Rosa FG, Pucillo LP, Coviello R, Pirro MR, Fiaschetti P, Candela M, Gabrielli A, Laganà B, Fiorilli M, Casato M. Influence of age and autoimmunity on liver disease in HCV-associated type II mixed cryoglobulinemia. Hum Immunol 2002; 63:751-7. [PMID: 12175729 DOI: 10.1016/s0198-8859(02)00423-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
It has been suggested that hepatitis C virus (HCV) infected patients with type II mixed cryoglobulinemia have less extensive liver damage than patients without cryoglobulinemia. We retrospectively evaluated 35 patients with type II mixed cryoglobulinemia associated with HCV infection, seeking for factors associated with normal alanine aminotransferase (ALT) values. The presence of anti-GOR and of other autoantibodies, including the recently described anti-LAG-3.1, was specifically investigated. Fifty-four percent of patients had anti-GOR, 46% anti-LAG-3.1, 40% anti-smooth muscle, 17% anti-nuclear, and 11% anti-liver-kidney microsome 1 antibodies. Anti-GOR was significantly (p = 0.037) associated with anti-LAG-3.1 but not with other autoantibodies. Persistently abnormal ALT levels were observed in 54% of patients. By univariate analyses, abnormal ALT was significantly associated with anti-GOR positivity (p = 0.018) and younger age (p = 0.03). Multivariate regression analysis confirmed that these variables were independently associated with abnormal ALT. Our data suggest that the presence of autoimmune manifestations as well as unidentified age-related host factor(s) may protect from liver injury in HCV-associated cryoglobulinemia.
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18
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Della Rossa A, Tavoni A, Baldini C, Bombardieri S. Treatment of chronic hepatitis C infection with cryoglobulinemia. Curr Opin Rheumatol 2002; 14:231-7. [PMID: 11981318 DOI: 10.1097/00002281-200205000-00006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Mixed cryoglobulinemia is characterized by a wide spectrum of manifestations that may vary from mild symptoms (such as purpura, arthralgias, and Raynaud phenomenon) to life-threatening conditions (such as acute abdomen, hyperviscosity syndrome, and renal involvement). Hepatitis C virus infection is considered the principal trigger of the disease. Therefore, the treatment not only should be tailored to the prevailing symptom but also take into account the presence of a chronic, often smoldering infection. Symptomatic therapies are to be used in cases of minor clinical manifestations and aggressive modalities in cases of life-threatening conditions. The use of aggressive cytotoxic regimens should actually be stopped and every potentially immunosuppressive drug should be used with caution. Antiviral medications are used with growing frequency. To date, a few small trials with interferon-alpha alone or in combination with ribavirin in mixed cryoglobulinemia have been conducted. This overview deals with the current approach to the management of mixed cryoglobulinemia, focusing in particular on antiviral treatment in hepatitis C virus infection with or without mixed cryoglobulinemia.
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Vassilopoulos D, Calabrese LH. Hepatitis C virus infection and vasculitis: implications of antiviral and immunosuppressive therapies. ARTHRITIS AND RHEUMATISM 2002; 46:585-97. [PMID: 11920393 DOI: 10.1002/art.10107] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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20
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Lamprecht P, Moosig F, Gause A, Herlyn K, Csernok E, Hansen H, Gross WL. Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis. Ann Rheum Dis 2001; 60:385-90. [PMID: 11247870 PMCID: PMC1753599 DOI: 10.1136/ard.60.4.385] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE To study immunological markers and compare these markers with standard measures for the clinical and immunological follow up of vasculitis activity in hepatitis C virus (HCV) associated cryoglobulinaemic vasculitis (CV). METHODS Serial serum samples from eight patients with newly diagnosed HCV associated CV were followed during interferon alpha treatment induced remission of the CV. Vasculitis activity and disease extent were evaluated with the Birmingham vasculitis activity score (BVAS) and disease extent index (DEI). Cryoglobulinaemia, complement levels (C3c, C4, and CH50), rheumatoid factor (RF), autoantibodies such as antinuclear antibodies, soluble interleukin 2 receptor (sIL2r), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble CD30 (sCD30) were determined. RESULTS All patients achieved either complete or partial remission of their CV during interferon alpha treatment. There was a significant reduction in vasculitis activity and disease extent (BVAS, DEI), cryoglobulinaemia, RF, sIL2r, sICAM-1, and sCD30. Complement C3c levels increased significantly during this period. Erythrocyte sedimentation rate and levels of complement C4 and CH50 did not change significantly. Both clinical measures (BVAS and DEI) correlated significantly only with C3c and sCD30. CONCLUSIONS Although this study was of only a small group of patients, it shows that BVAS and DEI as clinical measures and C3c and sCD30 as immunological markers may be useful in the follow up of disease activity of HCV associated CV. The data indicate that activity of the humoral (cryoglobulinaemia, RF, autoantibodies) and cellular (sIL2r, sICAM-1, sCD30) immune response and endothelial damage (sICAM-1) are found in HCV associated CV.
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Affiliation(s)
- P Lamprecht
- Department of Rheumatology, University of Lübeck, and Rheumaklinik Bad Bramstedt, Oskar-Alexander-Str. 26, 24576 Bad Bramstedt, Germany
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21
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Bcl-2 rearrangement in patients with chronic hepatitis C associated with essential mixed cryoglobulinemia type II. Blood 2000. [DOI: 10.1182/blood.v96.8.2910] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Hepatitis C virus (HCV) infection is found in 80% to 90% of patients with essential mixed cryoglobulinemia (EMC) type II, which is associated with monoclonal IgMk produced by monoclonal B cells. It was investigated whether bcl-2 rearrangement is associated with the clonal B-cell proliferation of EMC induced by hepatitis C. The study groups were composed of 15 patients with HCV and EMC, 12 patients with HCV without EMC, and 7 patients with chronic liver disease (CLD) unrelated to HCV. Fluorescence in situ hybridization with probes was applied to JH and to bcl-2 to study whether JH/bcl-2 translocation was present in these patients. Thirteen of 15 (86%) of patients with HCV-related EMC had the JH/bcl-2 translocation, a significantly higher rate than in HCV patients without EMC (16%; P < .001). Bcl-2 rearrangement was not detected in the patients with CLD not related to HCV. The JH/bcl2 translocation may constitute a pathogenetic link for the development of NHL in patients with HCV infection.
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Abstract
Hepatitis C virus (HCV) infection is found in 80% to 90% of patients with essential mixed cryoglobulinemia (EMC) type II, which is associated with monoclonal IgMk produced by monoclonal B cells. It was investigated whether bcl-2 rearrangement is associated with the clonal B-cell proliferation of EMC induced by hepatitis C. The study groups were composed of 15 patients with HCV and EMC, 12 patients with HCV without EMC, and 7 patients with chronic liver disease (CLD) unrelated to HCV. Fluorescence in situ hybridization with probes was applied to JH and to bcl-2 to study whether JH/bcl-2 translocation was present in these patients. Thirteen of 15 (86%) of patients with HCV-related EMC had the JH/bcl-2 translocation, a significantly higher rate than in HCV patients without EMC (16%; P < .001). Bcl-2 rearrangement was not detected in the patients with CLD not related to HCV. The JH/bcl2 translocation may constitute a pathogenetic link for the development of NHL in patients with HCV infection.
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Kondili LA, Taliani G, Tosti ME, De Bac C, Pasquazzi C, Mele A. Methodological issues in papers on IFN therapy: time for reappraisal. J Viral Hepat 2000; 7:184-95. [PMID: 10849260 DOI: 10.1046/j.1365-2893.2000.00214.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
We conducted an analytical review of 194 full papers on interferon (IFN) therapy for chronic hepatitis C to evaluate current methodology (i.e. study design, criteria for evaluating the efficacy of therapy and predictors of response). Of the papers evaluated, 64 were randomized controlled trials (RCT), 40 were non-randomized controlled trials (NRCT) and 90 were observational studies (OS). The methodological analysis was focused mainly on clinical trials. The number of patients enrolled in RCT was higher compared with the number enrolled in NRCT. Uniform enrolment criteria were used in less than 50% of the trials. Only 20% of RCT and 2.5% of NRCT used criteria for defining sample size. The response rate was calculated on an intention-to-treat basis in 36 of the RCT and in 14 of the NRCT. The outcome of treatment and the criteria employed to define the response to treatment were found to be far from standardized. In 51.5% of the RCT and 42.5% of the NRCT, normalization of alanine aminotransferase (ALT) level at the end of follow-up was the only marker of response studied. Only 57.6% of the trials considered histological evidence as an important outcome. Among the clinical trials, 71.1% evaluated predictors of good response to IFN therapy. In 51% of the OS, ALT normalization by the end of follow-up was the only criterion for defining response. In conclusion, to ensure a high level of reliability in comparing or combining the results of different studies, some basic general requirements must be followed when planning trials on antiviral therapy.
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Affiliation(s)
- L A Kondili
- Laboratorio di Epidemiologia e Biostatistica, Istituto Superiore di Sanit¿a, Roma, Italy
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Hadziyannis SJ, Vassilopoulos D. Complex management issues: management of HCV in the atypical patient. Best Pract Res Clin Gastroenterol 2000; 14:277-91. [PMID: 10890322 DOI: 10.1053/bega.1999.0076] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Some patients with chronic hepatitis C virus (HCV) infection demonstrate atypical features of presentation and clinical course. These features may be due to direct or indirect effects of the underlying HCV infection or may be part of a separate clinical syndrome. Patients that can be categorized as 'atypical' include immunosuppressed individuals (hypogammaglobulinaemic, co-infected with human immunodeficiency virus, recipients of solid organ or haematopoietic cell transplants, those with associated disease requiring chronic immunosuppressive therapy and patients with chronic renal failure on haemodialysis) as well as patients with various extra-hepatic (HCV-associated mixed cryoglobulinaemia, membranoproliferative glomerulonephritis etc) or autoimmune manifestations. Since many of these patients have been excluded from the large trials evaluating the efficacy of interferon-alpha alone or in combination with ribavirin, data regarding management are limited. In this chapter, the available information regarding the treatment of these patients is reviewed and the frequently encountered therapeutic dilemmas discussed. Finally, some reasonable therapeutic approaches are suggested while the need for controlled studies for these groups of patients is emphasized.
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Affiliation(s)
- S J Hadziyannis
- Academic Department of Medicine, Hippokration General Hospital, Athens, Greece
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25
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Abstract
Cryoglobulinemia may be found in a spectrum of disorders spanning clear-cut-B-cell neoplastic states, in which cryoprecipitation manifests as ischemic or occlusive vasculopathy, to a variety of immune complex diseases, in which vasculitis or glomerulonephritis may occur. Symptomatic cryoglobulinemia is many diseases, driven by and driving antibody-antigen responses, hepatic dysfunction, lymphoproliferation, and immune complexes. Distinguishing features that cause only some cryoglobulins to be symptomatic, elucidating the pathogenic mechanisms of HCV in cryoglobulin formation, and devising better therapies and more systematic evaluation of existing therapies are among the challenges for the future. Prognostication and classification will continue to rely on Brouet's classification (types I, II, and III), but additional features will probably include the presence or absence of HCV, HCV factors (genotype, titer), coexisting infections, B-cell clone burden, host factors, and immune system interactions (B- and T-cell idiotype networks, cytokines). Although antiviral therapy is a reasonable option for HCV-associated cryoglobulinemia, not all patients are HCV-positive, and only 60% to 80% of HCV-positive patients respond to IFN. In addition, not all patients tolerate IFN, and in those who do, the response is often short-lived once the treatment is discontinued. Only creative strategies, systematically studied, will provide long-awaited solutions.
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Affiliation(s)
- A Dispenzieri
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Del Rosso A, Generini S, Pignone A, Matucci-Cerinic M. Vasculitides secondary to systemic diseases. Clin Dermatol 1999; 17:533-47. [PMID: 10590846 DOI: 10.1016/s0738-081x(99)00060-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- A Del Rosso
- Department of Medicine, University of Florence, Italy
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Silvain C. [Antiviral treatment of hepatitis C virus infection]. Rev Med Interne 1999; 20 Suppl 3:331s-340s. [PMID: 10480183 DOI: 10.1016/s0248-8663(99)80505-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Hepatitis C virus infection is common and almost always chronic and can lead to cirrhosis and hepatocellular cancer. The primary goal of the treatment is virus eradication and the secondary is to reduce inflammation and liver cell damage. Interferon is the only effective therapy but disappearance of the virus is sustained in only 10 to 15%. The factors most closely associated with a response to treatment are absence of cirrhosis, low serum hepatitis C virus RNA level and genotype other than type 1. Recent studies have suggested that interferon treatment may reduce the subsequent risk of hepatocellular carcinoma in responders. The combination of interferon and oral ribavirin therapy increase the sustained response rate to about 40% in initial treatment and 50% for the treatment of relapse. The other therapeutic combination are less well documented. New agents such as hepatitis C virus-specific anti-protease may be available in the next future and treatment is evolving toward multiple-drug regimens.
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Affiliation(s)
- C Silvain
- Service d'hépato-gastroentérologie et d'assistance nutritive, CHU Jean Bernard, Poitiers, France
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Schott P, Pott C, Ramadori G, Hartmann H. Hepatitis C virus infection-associated non-cryoglobulinaemic monoclonal IgMkappa gammopathy responsive to interferon-alpha treatment. J Hepatol 1998; 29:310-5. [PMID: 9722214 DOI: 10.1016/s0168-8278(98)80018-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS An association of HCV infection with lymphoproliferative disorders, particularly B-cell non-Hodgkin's lymphoma has been described. In the majority of reported patients, mixed cryoglobulinaemia was present as well. Rarely, HCV-associated lymphoproliferative disorders have been observed in the absence of cryoglobulinaemia. In these latter patients, the response to interferon-alpha is largely unknown. CASE REPORT We report a case of an asymptomatic 31-year-old male with chronic HCV infection and non-cryoglobulinaemic monoclonal IgMkappa gammopathy responsive to interferon-alpha therapy. Prior to therapy, elevated plasma transaminase activities known for longer than a year, serum anti-HCV antibodies and HCV RNA detected by reverse transcriptase-polymerase chain reaction were present. Serum IgM concentration was markedly elevated, immunofixation demonstrated monoclonal serum IgM, and urine kappa-light chains were detected. Cryoglobulins were undetectable in several consecutive serum samples. Bone marrow aspirate and biopsy specimens were unremarkable. Further evaluation, e.g. by ultrasonography and radiography, did not reveal evidence for lymphoma. Treatment with interferon-alpha2a for 12 months resulted in a long-term sustained response to HCV infection and in a normalisation of serum IgM concentration. CONCLUSION Therefore, the corresponding effects of interferon-alpha on HCV infection and on a monoclonal B-cell population observed in the present case might suggest a pathogenetic connection, similarly, to what has been described for HCV and mixed cryoglobulinaemia. The molecular events, however, leading to HCV-induced monoclonal B-cell expansion remain unknown.
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Affiliation(s)
- P Schott
- Department of Medicine, Georg-August-Universität, Göttingen, Germany
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29
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De Rosa FG, Di Lullo L, Coviello R, Donnanno S, Laganà B, Casato M. Interferon-alpha treatment of hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol 1998; 28:355. [PMID: 9514550 DOI: 10.1016/0168-8278(88)80025-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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30
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Della Rossa A, Trevisani G, Bombardieri S. Cryoglobulins and cryoglobulinemia. Diagnostic and therapeutic considerations. Clin Rev Allergy Immunol 1998; 16:249-64. [PMID: 9773252 DOI: 10.1007/bf02737635] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- A Della Rossa
- Department of Internal Medicine, University of Pisa, Italy
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31
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Schott P, Polzien F, Müller-Issberner A, Ramadori G, Hartmann H. In vitro reactivity of cryoglobulin IgM and IgG in hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol 1998; 28:17-26. [PMID: 9537859 DOI: 10.1016/s0168-8278(98)80197-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Mixed cryoglobulinemia is frequently associated with chronic hepatitis C virus infection. We aimed to clarify the mechanism, kinetics and participating proteins in cryoprecipitate formation, which are still being debated. METHODS Eighteen patients with cryoglobulinemia were studied. Isolated serum cryoprecipitates and purified cryoglobulin IgM and IgG fractions were analyzed in vitro by turbidimetry for temperature-dependent complex formation. Immunoglobulin reactivity, i.e. in cryoprecipitates and in cryoglobulin-free sera, was studied using immunoblot and enzyme immunoassays. HCV RNA was detected by reverse transcriptase/polymerase chain reaction. RESULTS By turbidimetry, purified cryo-IgM precipitated (in the absence of HCV RNA) with cryo-IgG as well as with non-cryoglobulin IgG and with IgG Fc or F(ab')2 fragments. In contrast, purified cryo-IgG did not precipitate with non-cryoglobulin IgM. Anti-HCV IgG reactivity was found in cryoglobulin-free sera, in cryoprecipitates and in purified cryoglobulin IgG fractions. The respective titers were similar. Purified cryo-IgM did not react to HCV-encoded proteins. Binding of cryo-IgM to heterologous IgG was inhibited by intact IgG (up to a mean of about 52%) as well as by IgG Fc (33%) and F(ab')2 fragments (17%). Binding of cryo-IgM to IgG was enhanced at low temperature (4 degrees C vs. 37 degrees C), particularly for type III cryoglobulin IgM. CONCLUSIONS In hepatitis C virus-associated cryoglobulinemia the in vitro precipitate formation depended on cryo-IgM, while IgG appeared to act as an unspecific antigenic partner. Hepatitis C viral particles were probably not required. Cryo-IgM binding occurred primarily to intact IgG. Anti-HCV reactivity of either cryo-IgM or cryo-IgG was not necessary for precipitate formation. Regarding the pathogenesis, a direct hepatitis C virus protein-dependent stimulation of B-cells producing cryo-IgM seems to be unlikely.
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Affiliation(s)
- P Schott
- Department of Medicine, Georg-August-University, Göttingen, Germany
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