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Extrahepatic manifestations of HCV infection: facts and controversies

1999; Elsevier BV; Volume: 31; Issue: 2 Linguagem: Inglês

10.1016/s0168-8278(99)80239-6

1600-0641

Anna Linda Zignego, Christian Bréchot,

Liver Diseases and Immunity

The most documented extrahepatic manifestation of HCV infection is essential mixed cryoglobulinaemia (EMC). This topic has been the object of a previous, exhaustive, review by Lunel & Musset(1.Lunel F Musset L Hepatitis C virus infection and cryoglobulinemia.J Hepatol. 1998; 29: 848-855Abstract Full Text PDF PubMed Scopus (37) Google Scholar). Briefly, EMC is characterised by the presence of temperaturesensitive protein complexes: in type II EMC, cryoglobulins are composed of a monoclonal rheumatoid factor (RF) (usually IgMK) against polyclonal IgG. In type III EMC, all components are polyclonal. Since monoor polyclonal B lymphocyte expansion is responsible for cryoglobulin production, EMC may be considered a lymphoproliferative disorder (LPD). Due to the fact that EMC frequently coexists with bone marrow aspects of B-cell non-Hodgkin's lymphoma (NHL) and may evolve, in about 5–8% of cases, into a frank B-cell malignancy, it may be considered a "borderline" (benign/malignant) LPD. Evidence in favour of a pathogenetic link between EMC and HCV derives from a series of data including, first, the very high prevalence of HCV markers in EMC patients(1.Lunel F Musset L Hepatitis C virus infection and cryoglobulinemia.J Hepatol. 1998; 29: 848-855Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 2.Ferri C Greco F Longombardo G Palla P Moretti A Marzo E et al.Antibodies against hepatitis C virus in mixed cryoglobulinemia patients.Infection. 1991; 19: 417-420Crossref PubMed Scopus (64) Google Scholar, 3.Agnello V Chung RT Kaplan LM A role for hepatitis C virus infection in type II cryoglobulinemia.N Engl J Med. 1992; 327: 1490-1495Crossref PubMed Scopus (1331) Google Scholar, 4.Misiani R Bellavita P Fenili D Borelli G Marchesi D Massazza M et al.Hepatitis C virus infection in patients with essential mixed cryoglobulinemia.Ann Intern Med. 1992; 117: 573-577Crossref PubMed Scopus (539) Google Scholar, 5.Ferri C Marzo E Longombardo G Lombardini F La Civita L Vanacore R et al.Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial.Blood. 1993; 81: 1132-1136PubMed Google Scholar, 6.Marcellin P Descamps V Martinot-Peignoux M Larzul D Xu L Boyer N et al.Cryoglobulinemia with vasculitis associated with hepatitis C virus infection.Gastroenterology. 1993; 104: 272-277Abstract PubMed Google Scholar, 7.Cacoub P Fabiani FL Musset L Perrin M Frangeul L Leger JM et al.Mixed cryoglobulinemia and hepatitis C virus.Am J Med. 1994; 96: 124-132Abstract Full Text PDF PubMed Scopus (284) Google Scholar, 8.Zignego AL Ferri C Giannini C La Civita L Careccia G Longombardo G et al.Analysis of HCV infection in mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma: evidence for a pathogenetic role.Arch Virol. 1997; 142: 545-555Crossref PubMed Scopus (92) Google Scholar) with detection of HCV sequences in peripheral and bone marrow mononuclear cells in most patients, also in the absence of viraemia(9.Ferri C Monti M La Civita L Longombardo G Greco F Pasero G et al.Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia.Blood. 1993; 82: 3701-3704PubMed Google Scholar). The characteristic occurrence of EMC in patients with a longer history of HCV infection and/or elevated age suggests that EMC development depends on the length of infection(1.Lunel F Musset L Hepatitis C virus infection and cryoglobulinemia.J Hepatol. 1998; 29: 848-855Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 10.Pawlotsky JM Roudot-Thoraval F Simmonds P Mellor J Ben Yahia MB Andre C et al.Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes.Ann Intern Med. 1995; 122: 169-173Crossref PubMed Scopus (350) Google Scholar, 11.Zignego AL Ferri C Giannini C Monti M La Civita L Careccia G et al.Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia.Ann Intern Med. 1996; 124: 31-34Crossref PubMed Google Scholar). In the single patient, however, inherited or acquired factors predisposing to LPDs may accelerate the occurrence of cryoglobulinaemia and worsen corresponding clinical manifestations, as also suggested by observations made in patients receiving a liver graft for HCV-related cirrhosis(12.Gournay J Ferrell LD Roberts JP Ascher NL Wright TL Lake JR Cryoglobulinemia presenting after liver transplantation.Gastroenterology. 1996; 110: 265-270Abstract Full Text PDF PubMed Scopus (45) Google Scholar). With respect to viral factors possibly involved in the pathogenesis of EMC/HCV, the majority of studies agree that no HCV genotype is specifically related to EMC, and that the more prevalent genotype observed in HCV-related EMC is the one most prevalent in the general HCV-positive population of the same geographical area.(1.Lunel F Musset L Hepatitis C virus infection and cryoglobulinemia.J Hepatol. 1998; 29: 848-855Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 11.Zignego AL Ferri C Giannini C Monti M La Civita L Careccia G et al.Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia.Ann Intern Med. 1996; 124: 31-34Crossref PubMed Google Scholar, 13.Pozzato G Mazzaro C Crovatto M Modolo ML Ceselli S Mazzi G et al.Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia.Blood. 1994; 84: 3047-3053PubMed Google Scholar). However, a high prevalence of genotype 2 in EMC patients was observed in Italy(11.Zignego AL Ferri C Giannini C Monti M La Civita L Careccia G et al.Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia.Ann Intern Med. 1996; 124: 31-34Crossref PubMed Google Scholar, 13.Pozzato G Mazzaro C Crovatto M Modolo ML Ceselli S Mazzi G et al.Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia.Blood. 1994; 84: 3047-3053PubMed Google Scholar, 14.Monteverde A Ballare M Pileri S Hepatic lymphoid aggregates in chronic hepatitis C and mixed cryoglobulinemia.Springer Semin Immunopathol. 1997; 19: 99-110Crossref PubMed Scopus (87) Google Scholar, 15.Zehender G De Maddalena C Monti G Ballare M Saccardo F Piconi S et al.HCV genotypes in bone marrow and peripheral blood mononuclear cells of patients with mixed cryoglobulinemia.Clin Exp Rheumatol. 1995; 13S: S87-S90Google Scholar). In some cases, this viral type was only observed in lymphatic cells(11.Zignego AL Ferri C Giannini C Monti M La Civita L Careccia G et al.Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia.Ann Intern Med. 1996; 124: 31-34Crossref PubMed Google Scholar). Therefore, it is still debatable whether or not different viral types might exert a lesser or more important influence in favouring the appearance of LPDs. Indeed, it is interesting to note the intense stimulation of the lymphatic system reported during HCV type 2 infection(16.Cerino A Silini E Brambilla S Asti M Bellati G Lisa A et al.Serological response to HCV hypervariable region 1 are mainly cross-reactive and genotype-dependent.J Hepatol. 1997; 26S1: 62Google Scholar, 17.Missale G Cariani E Lamonaca V Ravaggi A Rossini A Bertoni R et al.Effects of interferon treatment on the antiviral T-cell response in hepatitis C virus genotype 1b- and genotype 2c-infected patients.Hepatology. 1997; 26: 792-797Crossref PubMed Scopus (65) Google Scholar) as well as the recently observed high frequency of this type in different HCV-positive B-cell LPDs(18.Silvestri F Barillari G Fanin R Pipan C Falasca E Salmaso F et al.The genotype of the hepatitis C virus in patients with HCV-related B cell non-Hodgkin's lymphoma.Leukemia. 1997; 11: 2157-2161Crossref PubMed Scopus (60) Google Scholar, 19.Andreone P Zignego AL Cursaro C Gramenzi A Gherlinzoni F Fiorino S et al.Prevalence of monoclonal gammopathies in patients with hepatitis C virus infection.Ann Intern Med. 1998; 129: 294-298Crossref PubMed Scopus (107) Google Scholar). Differences in the geographical distribution of this subtype may account, at least in part, for the discrepancies among available data on the prevalence of HCV genotypes in EMC patients. Results of interferon treatment in EMC patients represent an indirect proof for the pathogenetic link between EMC and HCV infection(1.Lunel F Musset L Hepatitis C virus infection and cryoglobulinemia.J Hepatol. 1998; 29: 848-855Abstract Full Text PDF PubMed Scopus (37) Google Scholar). Controlled trials have now defined the efficacy of IFN alpha in the treatment of EMC. Response to IFN can be achieved in more than 50% of patients and includes improvement of cutaneous vasculitis and renal function, reduction in hepatitis C viraemia, serum cryoglobulin concentration, and IgM RF synthesis(5.Ferri C Marzo E Longombardo G Lombardini F La Civita L Vanacore R et al.Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial.Blood. 1993; 81: 1132-1136PubMed Google Scholar, 20.Misiani R Bellavita P Fenili D Vicari O Marchesi D Sironi PL et al.Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus.N Engl J Med. 1994; 330: 751-756Crossref PubMed Scopus (639) Google Scholar). However, almost 80% of responders eventually have a clinical and biochemical relapse. Additional studies are therefore required to improve the outcome and extension of this therapy. The association between HCV infection and B-cell non-Hodgkin's lymphoma (NHL) has been reported both in patients with HCV-related type II EMC (EMC/NHL) (13.Pozzato G Mazzaro C Crovatto M Modolo ML Ceselli S Mazzi G et al.Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia.Blood. 1994; 84: 3047-3053PubMed Google Scholar, 21.Ferri C Monti M La Civita L Careccia G Mazzaro C Longombardo G et al.Hepatitis C virus infection in non-Hodgkin's B-cell lymphoma complicating mixed cryoglobulinaemia.Eur J Clin Invest. 1994; 24: 781-784Crossref PubMed Scopus (78) Google Scholar, 22.La Civita L Zignego AL Monti M Longombardo G Pasero G Ferri C Mixed cryoglobulinemia as a possible preneoplastic disorder.Arthritis Rheum. 1995; 38: 1859-1860Crossref PubMed Scopus (50) Google Scholar, 23.Franzin F Efremov DG Pozzato G Tulissi P Batista F Burrone OR Clonal B-cell expansions in peripheral blood of HCV-infected patients.Br J Haematol. 1995; 90: 548-552Crossref PubMed Scopus (164) Google Scholar) and in patients without EMC (non-EMC-associated or "idiopathic" NHL) (24.Zignego AL Ferri C Giannini C La Civita L Careccia G Longombardo G et al.Hepatitis C virus infection in mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma: evidence for a pathogenetic role.Arch Virol. 1997; 142: 545-555Crossref PubMed Scopus (68) Google Scholar, 25.Izumi T Sasaki R Tsunoda S Akutsu M Okamoto H Miura Y B cell malignancy and hepatitis C virus infection.Leukemia. 1997; S3: 516-518Google Scholar, 26.Satoh T Yamada T Nakano S Tokunaga O Kuramochi S Kanai T et al.The relationship between primary splenic malignant lymphoma and chronic liver disease associated with hepatitis C virus infection.Cancer. 1997; 80: 1981-1988Crossref PubMed Scopus (28) Google Scholar, 27.Sikuler E Shnaider A Zilberman D Hilzenrat N Shemer-Avni Y Neumann L et al.Hepatitis C virus infection and extrahepatic malignancies.J Clin Gastroenterol. 1997; 24: 87-89Crossref PubMed Scopus (25) Google Scholar, 28.Zuckerman E Zuckerman T Levine AM Douer D Gutekunst K Mizokami M et al.Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma.Ann Intern Med. 1997; 127: 423-428Crossref PubMed Scopus (363) Google Scholar, 29.Ferri C La Civita L Monti M Longombardo G Pasero G Zignego AL Can type C hepatitis infection be complicated by malignant lymphoma?.Lancet. 1995; 346: 1426-1427PubMed Scopus (84) Google Scholar, 30.Ferri C Caracciolo F Zignego AL La Civita L Monti M Longombardo G et al.Hepatitis C virus infection in patients with non-Hodgkin's lymphoma.Br J Haematol. 1994; 88: 392-394Crossref PubMed Scopus (422) Google Scholar, 31.Ferri C Caracciolo F La Civita L Monti M Longombardo G Zignego AL Hepatitis C virus infection and B-cell lymphomas.Eur J Cancer. 1994; 30A: 1591-1592Abstract Full Text PDF PubMed Scopus (27) Google Scholar, 32.Zignego AL Ferri C Innocenti F Giannini C Monti M Bellesi G et al.Lack of preferential localization of tumoral mass in B-cell non-Hodgkin's lymphoma associated with hepatitis C virus infection.Blood. 1997; 89: 3066-3068PubMed Google Scholar, 33.Luppi M Grazia Ferrari M Bonaccorsi G Longo G Narni F Barozzi P et al.Hepatitis C virus infection in subsets of neoplastic lymphoproliferations not associated with cryoglobulinemia.Leukemia. 1996; 10: 351-355PubMed Google Scholar, 34.Silvestri F Pipan C Barillari G Zaja F Fanin R Infanti L et al.Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders.Blood. 1996; 87: 4296-4301PubMed Google Scholar, 35.De Vita S Sacco C Sansonno D Gloghini A Dammacco F Crovatto M et al.Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection.Blood. 1997; 90: 776-782PubMed Google Scholar, 36.Ferri C La Civita L Caracciolo F Bellesi G Zignego AL Hepatitis C virus and lymphoproliferative disorders.Blood. 1997; 88: 4730Google Scholar, 37.De Rosa G Gobbo ML De Renzo A Notaro R Garofalo S Grimaldi M et al.High prevalence of hepatitis C virus infection in patients with B-cell lymphoproliferative disorders in Italy.Am J Hematol. 1997; 55: 77-82Crossref PubMed Scopus (113) Google Scholar). As in EMC-associated NHL, "idiopathic" NHL also appears after long-lasting HCV infection (29.Ferri C La Civita L Monti M Longombardo G Pasero G Zignego AL Can type C hepatitis infection be complicated by malignant lymphoma?.Lancet. 1995; 346: 1426-1427PubMed Scopus (84) Google Scholar). Many of these studies have been, so far, performed in Italy and there are some discordant reports from other geographical areas (38.Brind AM Watson JP Burt A Kestevan P Wallis J Proctor SJ et al.Non-Hodgkin's lymphoma and hepatitis C virus infection.Leuk Lymphoma. 1996; 21: 127-130Crossref PubMed Scopus (64) Google Scholar, 39.McColl MD Singer IO Tait RC McNeil IR Cumming RL Hogg RB The role of hepatitis C virus in the aetiology of non-Hodgkins lymphoma - a regional association?.Leuk Lymphoma. 1997; 26: 127-130PubMed Google Scholar). With respect to the possible association between HCV infection and different LPDs, a common observation isthe lack of an associationbetween HCV and non-B-LPDs (i.e., Hodgkin's lymphoma or T-NHL)(32.Zignego AL Ferri C Innocenti F Giannini C Monti M Bellesi G et al.Lack of preferential localization of tumoral mass in B-cell non-Hodgkin's lymphoma associated with hepatitis C virus infection.Blood. 1997; 89: 3066-3068PubMed Google Scholar, 37.De Rosa G Gobbo ML De Renzo A Notaro R Garofalo S Grimaldi M et al.High prevalence of hepatitis C virus infection in patients with B-cell lymphoproliferative disorders in Italy.Am J Hematol. 1997; 55: 77-82Crossref PubMed Scopus (113) Google Scholar). The relationship between HCV infection and other B-cell LPDs, such as chronic lymphocytic leukaemia, Waldenström's macroglobulinaemia, multiple myeloma, and different monoclonal gammopathies, has been suggested and remains open to discussion(19.Andreone P Zignego AL Cursaro C Gramenzi A Gherlinzoni F Fiorino S et al.Prevalence of monoclonal gammopathies in patients with hepatitis C virus infection.Ann Intern Med. 1998; 129: 294-298Crossref PubMed Scopus (107) Google Scholar, 25.Izumi T Sasaki R Tsunoda S Akutsu M Okamoto H Miura Y B cell malignancy and hepatitis C virus infection.Leukemia. 1997; S3: 516-518Google Scholar, 37.De Rosa G Gobbo ML De Renzo A Notaro R Garofalo S Grimaldi M et al.High prevalence of hepatitis C virus infection in patients with B-cell lymphoproliferative disorders in Italy.Am J Hematol. 1997; 55: 77-82Crossref PubMed Scopus (113) Google Scholar, 40.La Civita L Zignego AL Monti M Longombardo G Greco F Pasero G et al.Type C hepatitis and chronic lymphocytic leukaemia. Type C hepatitis and chronic lymphocytic leukaemia.Eur J Cancer. 1996; 32A: 1819-1820Abstract Full Text PDF PubMed Scopus (6) Google Scholar). Taken together, the available data suggest the hypothesis that HCV infection is associated with B cell LPDs of different clinico-pathological characteristics, probably representing a predisposing factor that acts in a remote stage of their pathogenesis. There are a series of disorders for which an association with HCV infection has been suggested, frequently without sufficient confirmation. These include idiopathic pulmonary fibrosis, lichen planus, Sjögren syndrome, Mooren corneal ulcers, autoimmune thyroiditis, and porphyria cutanea tarda. A pathogenetic link between HCV infection and some of these disorders has been suggested also on the basis of the response to antiviral therapy(41.Moazami G Auran JD Florakis GJ Wilson SE Srinivasan DB Interferon treatment of Mooren's ulcers associated with hepatitis C.Am J Ophthalmol. 1995; 119: 365-366Abstract Full Text PDF PubMed Scopus (45) Google Scholar). Furthermore, in some cases, anti-viral treatment with interferon has been suggested actually to be responsible for the association. This may be the case in autoimmune phenomena involving the thyroid. A high prevalence of thyroid dysfunction and anti-thyroid antibodies including thyroid microsomal, thyreoglobulin and thyroid peroxidase antibodies, has been found in up to 30% of chronic HCV infections. However, some investigations were unable to find either a higher prevalence of HCV infection in patients with Hashimoto's thyroiditis(42.Wong S Mehta AE Faiman C Berard L Ibbott T Minuk GY Absence of serologic evidence for hepatitis C virus infection in patients with Hashimoto's thyroiditis.Hepatogastroenterology. 1996; 43: 420-421PubMed Google Scholar), or an increased prevalence of thyroid dysfunction and antithyroid peroxidase antibodies in blood donors with HCV infection in comparison to controls(43.Boadas J Rodriguez-Espinosa J Enríquez J Miralles F Martinez-Cerezo FJ González P et al.Prevalence of thyroid autoantibodies is not increased in blood donors with hepatitis C virus infection.J Hepatol. 1995; 22: 611-615Abstract Full Text PDF PubMed Scopus (71) Google Scholar). These patients may be particularly susceptible to the development of Hashimoto's thyroiditis or Grave's disease following therapy with alpha interferon and to the direct reduction by r-IFN-alpha of the intrathyroidal organification of iodine(44.Roti E Minelli R Giuberti T Marchelli S Schianchi C Gardini E et al.Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha.Am J Med. 1996; 101: 482-487Abstract Full Text PDF PubMed Scopus (171) Google Scholar). In fact, thyroid dysfunction is not infrequently observed in patients receiving r-IFN-alpha therapy because of chronic active hepatitis of different aetiologies, and IFN-alpha therapy may induce, reveal or exacerbate various autoimmune-related disorders. In light of these data it is possible that cooperation between IFN and HCV takes place in treated patients and that HCV infection plays a contributory role in the pathogenesis of such disorders. Other associations may, at least in part, overlap with the already-described extrahepatic manifestations of HCV infection. This is the case, for example, in the suggested link between HCV infection and Sjögren's syndrome (SS) or idiopathic pulmonary fibrosis (IPF). Different viruses (i.e., herpes virus and retrovirus) have been suspected to play a role in triggering lymphoid proliferation, which, like EMC, may culminate in the development of a malignant lymphoma. A close relationship between SS and HCV has been shown by epidemiological studies(45.Aceti A Taliani G Sorice M Amendolea MA HCV and Sjögren's syndrome.Lancet. 1992; 339: 1425-1426Abstract PubMed Scopus (51) Google Scholar, 46.Haddad J Deny P Munz-Gotheil C Ambrosini JC Trinchet JC Pateron D et al.Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease.Lancet. 1992; 339: 321-323Abstract PubMed Scopus (525) Google Scholar) and the coexistence of EMC in patients with HCV-associated SS has been suggested(46.Haddad J Deny P Munz-Gotheil C Ambrosini JC Trinchet JC Pateron D et al.Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease.Lancet. 1992; 339: 321-323Abstract PubMed Scopus (525) Google Scholar). However, the pathogenetic role of HCV infection in the development of SS, as well as the characteristics distinguishing classical SS from the HCV-associated syndrome, have been an object of debate(47.Pirisi M Scott C Fabris C Ferraccioli G Soardo G Ricci R et al.Mild sialoadenitis: a common finding in patients with hepatitis C virus infection.Scand J Gastroenterol. 1994; 29: 940-942Crossref PubMed Scopus (64) Google Scholar). More recently, observations of the presence of a typical autoimmune sialadenitis in HCV-positive subjects, similar to that described in primary SS(48.Coll J Gambus G Corominas J Tomas S Esteban JI Guardia J Immunohistochemistry of minor salivary gland biopsy specimens from patients with Sjögren's syndrome with and without hepatitis C virus infection.Ann Rheum Dis. 1997; 56: 390-392Crossref PubMed Scopus (54) Google Scholar, 49.Scott CA Avellini C Desinan L Pirisi M Ferraccioli GF Bardus P et al.Chronic lymphocytic sialoadenitis in HCV-related chronic liver disease: comparison of Sjögren's syndrome.Histopathology. 1997; 30: 41-48Crossref PubMed Scopus (85) Google Scholar), as well as experimental data, suggest that HCV might effectively be involved in the pathogenesis of this syndrome. In this respect, transgenic mice carrying the HCV envelope genes have recently been shown to develop an exocrinopathy involving salivary and lacrymal glands, which strongly resembles SS(50.Koike K Moriya K Ishibashi K Yotsuyanagi H Shintani Y Fujie H et al.Sialadenitis histologically resembling Sjögren syndrome in mice transgenic for hepatitis C virus envelope genes.Proc Natl Acad Sci USA. 1997; 94: 233-236Crossref PubMed Scopus (215) Google Scholar). In consideration of the frequent association of SS with EMC in HCV-positive patients, as well as of the possible evolution of SS into a B-cell NHL(35.De Vita S Sacco C Sansonno D Gloghini A Dammacco F Crovatto M et al.Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection.Blood. 1997; 90: 776-782PubMed Google Scholar, 36.Ferri C La Civita L Caracciolo F Bellesi G Zignego AL Hepatitis C virus and lymphoproliferative disorders.Blood. 1997; 88: 4730Google Scholar, 51.Tzioufas AG Manoussakis MN Costello R Silis M Papadopoulos NM Moutsopoulos HM Cryoglobulinemia in autoimmune rheumatic diseases. Evidence of circulating monoclonal cryoglobulins in patients with primary Sjögren's syndrome.Arthritis Rheum. 1986; 29: 1098-1104Crossref PubMed Scopus (100) Google Scholar, 52.Luppi M Grazia Ferrari M Bonaccorsi G Longo G Narni F Barozzi P et al.Hepatitis C virus infection in subsets of neoplastic lymphoproliferations not associated with cryoglobulinemia.Leukemia. 1996; 10: 351-355PubMed Google Scholar), the syndrome observed in infected patients may be interpreted as one of the possible clinical manifestations of the HCV-related lymphoproliferative disorder. A pathogenetic link between HCV infection and IPF has been suggested because of the higher frequency of HCV markers in IPF patients than in normal controls(53.Ueda N Shah SV Apoptosis.J Lab Clin Med. 1994; 124: 169-177PubMed Google Scholar, 54.Ohta K Ueda T Nagai S Yamada K Yamaguchi M Nakano J et al.Pathogenesis of idiopathic pulmonary fibrosis: is hepatitis C virus involved?.Nippon Kyobu Shikkan Gakkai Zasshi. 1993; 31S: 32-35Google Scholar) and the observation that some patients with HCV-positive chronic hepatitis treated with IFN-alpha developed pulmonary fibrosis. Moreover, there was an increased count of lymphocytes and neutrophils in bronchoalveolar lavage fluid in patients with HCV chronic infection(55.Yamaguchi S Kubo K Fujimoto K Honda T Sekiguchi M Sodeyama T Analysis of bronchoalveolar lavage fluid in patients with chronic hepatitis C before and after treatment with interferon alpha.Thorax. 1997; 52: 33-37Crossref PubMed Scopus (47) Google Scholar), suggesting that HCV infection may trigger alveolitis(55.Yamaguchi S Kubo K Fujimoto K Honda T Sekiguchi M Sodeyama T Analysis of bronchoalveolar lavage fluid in patients with chronic hepatitis C before and after treatment with interferon alpha.Thorax. 1997; 52: 33-37Crossref PubMed Scopus (47) Google Scholar). However, there are conflicting epidemiological data, mainly from the UK, making this association an object of debate(56.Irving WL Day S Johnston ID Idiopathic pulmonary fibrosis and hepatitis C virus infection.Am Rev Respir Dis. 1993; 148: 1683-1684Crossref PubMed Google Scholar). The fact that EMC may be complicated by interstitial lung involvement suggests that the association between HCV and IPF may be indirect, at least in some cases, and due to surrounding HCV-related EMC. In a study we recently performed in a group of HCV chronically infected patients with IPF, interstitial lung involvement appeared medially 4.5±3.2 S.D. years after the clinical onset of chronic hepatitis and was associated with somerheumatic symptoms and serum cryoglobulins and/or autoantibodies(57.Ferri C La Civita L Fazzi P Solfanelli S Lombardini F Begliomini E et al.Interstitial lung fibrosis and rheumatic disorders in patients with hepatitis C virus infection.Br J Rheumatol. 1997; 36: 360-365Crossref PubMed Google Scholar). Apart from the palpable purpura due to leukocytoclastic vasculitis, which is the most frequently observed dermatological manifestation of HCV-related EMC, HCV infection has also been associated with a series of different cutaneous disorders, including sporadic porphyria cutanea tarda (PCT) and cutaneous and/or mucosal lichen planus (LP). A strong association between sporadic PCT and HCV infection has been proposed on the basis of the observation of a high prevalence (>50%) of HCV markers in those patients, mostly in studies from southern Europe(58.Piperno A D'Alba R Roffi L Pozzi M Farina A Vecchi L et al.Hepatitis C virus infection in patients with idiopathic hemochromatosis (IH) and porphyria cutanea tarda (PCT).Arch Virol Suppl. 1992; 4: 215-216Crossref PubMed Scopus (35) Google Scholar, 59.Fargion S Piperno A Cappellini MD Sampietro M Fracanzani AL Romano R et al.Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association.Hepatology. 1992; 16: 1322-1326Crossref PubMed Scopus (325) Google Scholar, 60.Ferri C Baicchi U la Civita L Greco F Longombardo G Mazzoni A et al.Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda.Eur J Clin Invest. 1993; 23: 851-855Crossref PubMed Google Scholar, 61.Navas S Bosch O Castillo I Marriott E Carreno V Porphyria cutanea tarda and hepatitis C and B viruses infection: a retrospective study.Hepatology. 1995; 21: 279-284PubMed Google Scholar). In several studies, no alterations in porphyrin metabolism were demonstrated in HCV-positive patients without PCT(62.Hussain I Hepburn NC Jones A O'Rourke K Hayes PC The association of hepatitis C viral infection with porphyria cutanea tarda in the Lothian region of Scotland.Clin Exp Dermatol. 1996; 21: 283-285Crossref PubMed Scopus (28) Google Scholar, 63.O'Reilly FM Darby C Fogarty J O'Moore R Courtney MG O'Connor J et al.Porphyrin metabolism in hepatitis C infection.Photodermatol Photoimmunol Photomed. 1996; 12: 31-33Crossref PubMed Scopus (31) Google Scholar), suggesting that HCV infection probably acts as a triggering factor in genetically predisposed subjects. In contrast, preliminary data suggest that HCV infection induces a decreased concentration of uroporphyrinogen decarboxylase (URO-D), the enzyme responsible for PCT manifestations, also in patients with no evidence of PCT (S. Fargion, personal communication). In addition, a significantly higher frequency of immunological alterations in HCV-positive patients with PCT, including anti-GOR antibodies, ANA, ASMA, anti-LKM1, RF and mixed cryoglobulins than in healthy subjects and patients with different immunological diseases was observed, suggesting the pathogenetic importance of HCV-related autoimmunity in inducing the precipitation of this metabolic disorder(64.Ferri C Baicchi U la Civita L Greco F Longombardo G Mazzoni A et al.Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda.Eur J Clin Invest. 1993; 23: 851-855Crossref PubMed Scopus (90) Google Scholar). Lichen planus is another skin disorder which is thought to be associated with HCV infection on the basis of the observation of an increased frequency of HCV infection among LP patients, in particular in Italy and Japan(65.Nagao Y Sata M Tanikawa K Itoh K Kameyama T Lichen planus and hepatitis C virus in the northern Kyushu region of Japan.Eur J Clin Invest. 1995; 25: 910-914Crossref PubMed Scopus (162) Google Scholar, 66.Tanei R Watanabe K Nishiyama S Clinical and histopathologic analysis of the relationship between lichen planus and chronic hepatitis C.J Dermatol. 1995; 22: 316-323PubMed Google Scholar, 67.Carrozzo M Gandolfo S Carbone M Colombatto P Broccoletti R Garzino-Demo P et al.Hepatitis C virus infection in Italian patients with oral lichen planus: a prospective case-control study.J Oral Pathol Med. 1996; 25: 527-533Crossref PubMed Scopus (149) Google Scholar). However, these results have not been confirmed by other reports from other geographical areas and this association remains controversial. In addition, IFN treatment has been shown to trigger LP in some HCV-positive cases(68.Nagao Y Sata M Ide T Suzuki H Tanikawa K Itoh K et al.Development and exacerbation of oral lichen planus during and after interferon therapy for hepatitis C.Eur J Clin Invest. 1996; 26: