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CONTROVERSY

The worldwide prevalence of hepatitis C virus (HCV) is estimated to be around 3%, representing approximately 170 million infected individuals. Morbidity associated with HCV infection is due not only to the sequelae of chronic liver disease but also to a variety of extrahepatic manifestations, including that involving the oral cavity. In the review that follows, Drs. Carrozzo and Gandolfo discuss the controversial role of HCV in the mechanisms underlying the pathogenesis of two oral conditions—Sjögren's-like sialadenitis and oral lichen planus. — Olav Alvares, Editor

ORAL DISEASES POSSIBLY ASSOCIATED WITH HEPATITIS C VIRUS
M. Carrozzo* S. Gandolfo Department of Biomedical Sciences and Human Oncology, Oral Medicine Section, C. so Dogliotti 14, University of Turin, I-10126 Torino, Italy; *corresponding author, marco.carrozzo@unito.it ABSTRACT: Morbidity associated with hepatitis C virus (HCV) infection can involve a variety of extrahepatic conditions, including lichen planus (LP) and sialadenitis, predominantly or exclusively involving the oral region, conditions which have been largely neglected in reviews. The literature suggests that HCV-infected patients may frequently have Sjögren-like sialadenitis with mild clinical symptoms, whereas oral LP may be significantly associated with HCV infections in Southern Europe and Japan but not in Northern Europe. These geographical differences could be related to immunogenetic factors such as the HLA-DR6 allele, significantly expressed in Italian patients with OLP and HCV. Analysis of experimental data suggests that HCV could be involved in the pathogenesis of both these diseases. Moreover, parotid lymphoma may arise in patients with sialadenitis, mainly with type II cryoglobulinemia. Little attention has been paid to oral health needs in HCV-infected patients and the variable effect of interferon-alpha therapy on oral tissues. Further research is needed, because of the potentially great influence of oral diseases possibly linked to HCV on the quality of life of millions of patients. Key words. Hepatitis C virus, lichen planus, oral lichen planus, sialadenitis, Sjögren's syndrome.

(I) Introduction

H

epatitis C virus (HCV) is an enveloped, single-stranded positive-sense RNA virus that was isolated in 1989 from a chimpanzee chronically infected by contamination with a human factor VIII concentrate (Choo et al., 1989). Although details of HCV replication are not known, it is thought to take place in the cytoplasm, where, among other products, negative-sense viral RNA (vRNA), replicative double-stranded forms, and non-structural proteins are synthesized. Their presence can thus be used as evidence that virus multiplication, as opposed to passive transportation, is occurring (Negro et al., 1999). HCV has an extremely variable genome, and six distinct genotypes and multiple subtypes have been identified (Pileri et al., 1998). Furthermore, sequence variants forming a quasispecies may circulate within an individual, possibly as a consequence of ongoing immune surveillance and viral mutations (Toyoda et al., 1998). HCV is presently considered the main etiologic agent of both blood-borne and sporadic non-A non-B hepatitis, and is one of the major causes of chronic liver disease worldwide. The overall estimated prevalence of HCV infection is 3%, representing approximately 170 million infected people world-

wide. However, there is great geographic variation in the prevalence of infection. On the basis of studies among blood donors (Wasley and Alter, 2000), the lowest prevalence of antiHCV antibodies (0.01-0.1%) is in the United Kingdom and Scandinavia, followed by slightly higher rates (0.2-0.05%) in Western Europe, North America, most areas of Central and South America, Australia, and South Africa; intermediate rates (1-5%) are reported in Brazil, Eastern Europe, the Mediterranean area, the Middle East, the Indian subcontinent, and parts of Africa and Asia, and the highest HCV prevalence is reported in Egypt (17-26%). The natural history of HCV infection is difficult to assess because of the usually silent onset of the acute phase and the few symptoms seen during the early stages of chronic infection. Acute infection leads to chronic infection in the majority of persons (up to 80%), of whom 20% will eventually develop cirrhosis (Di Bisceglie, 1998). Once cirrhosis is established, the risk of the subject's developing hepatocellular carcinoma is approximately 1 to 4% per year (Colombo et al., 1991). Morbidity associated with HCV infection is due not only to the sequelae of chronic liver disease, but also to a variety of extrahepatic manifestations (Table 1). Most of these are immune-mediated, possibly as a result of virus-dependent pro-

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Xerophthalmia.. 116 Crit Rev Oral Biol Med 14(2):115-127 (2003) . A series of extrahepatic cell types possibly supporting HCV replication has been proposed. 1994 Pirisi et al. lichen planus (LP) and sialadenitis. 2000 Henderson et al. 1993 Pawlotsky et al. 1999). 2000. 1994 Boscagli et al. 1992 Guisset et al. adrenal gland. 1999 Cacoub et al. This was reinforced by a French study finding that 57% of HCV-associated chronic liver disease patients exhibited a grade 3 TABLE 2 Lacrimal or Salivary Abnormality in Patients with HCV Infection Histological Evidence of Sialadenitis (%) 100 49 20 77 60.6h Positive Schirmer test. in most cases. 2002 a b c d e f g h n 28 22 50 61 22 32 23 20 21 1614 321 87 40 45 74 Country France Italy France France France Italy France Italy Sweden France France Australia UK France Spain Xerostomia (%) 35. Percentage of patients with hyposalivation measured by mean of the Salivette system not available. Roy and Bagg. 1994a Poet et al..4d 33d 50f NAg 16. thyroid.. 1997 Verbaan et al. 1998.3a 14a. Lodi et al.. 2001 Loustaud-Ratti et al. two of the most frequently reported extrahepatic manifestations of HCV infection... (II) Sjögren-like Sialadenitis Cases of chronic hepatitis C with mixed cryoglobulinemia and signs of Sjögren's syndrome (SS) first suggested a possible link between SS and HCV infection. 1992 Almasio et al. 2001). Unstimulated and stimulated whole sialometry. lung. and skin cells (De Vita et al.. Notably.7 5 5 11 12 18...TABLE 1 Extrahepatic Manifestations of HCV Infection Hematologic and lymphoid Mixed cryoglobulinemia Aplastic anemia Idiopathic thrombocytopenia Non-Hodgkin's B-cell lymphoma Endocrine Hashimoto's disease Hypothyroidism Hyperthyroidism Diabetes mellitus Dermatologic Leukocytoclastic vasculitis Porphyria cutanea tarda Lichen planus Polyarteritis nodosa Erythema multiforme Erythema nodosum Malakoplakia Urticaria Pruritus Psoriasis Necrolytic acral erythema Still's disease Unilateral nevoid telangiectasia Disseminated superficial porokeratosis Acquired epidermolysis bullosa Salivary gland and ocular Sialadenitis Mooren corneal ulcer Uveitis Renal Glomerulonephritis Neuromuscular and joints Muscle weakness Latent muscular abnormalities Peripheral neuropathy Arthritis/arthralgias Rheumatoid arthritis Autoimmune and miscellaneous Pulmonary fibrosis Pulmonary vasculitis Hypertrophic cardiomyopathy CRST syndrome Antiphospholipid syndrome Granulomas Autoimmune hepatitis types 1 and 2 Presence of autoantibodies Oral carcinoma liferation of monoclonal or polyclonal lymphocytes (Bonkovsky and Mehta.. Laskus et al...4 8 62 8 Hyposalivation (%) 13. One approach used to study the pathogenesis of HCVassociated disease is to follow its replicative pattern in infected tissue and to establish anatomoclinical correlations. the salivary flow rates in HCV+ve patients were significantly lower than those in healthy controls.8 0 11 80 Lacrimal Abnormality (%) 10. and gastric. 45% of the patients had not further defined "lacrimal dysfunctions". 2000. focused on its oral manifestations. Nagao et al.. 2000 Coates et al.. are available (Lodi and Porter. not significantly altered compared with healthy controls.7 0 0 30.. Unstimulated whole sialometry.. Stimulated whole sialometry. involve the oral region predominantly or exclusively.b 50c 26a 0a 57a 11e 12e 31e - Reference Haddad et al.. including peripheral blood mononuclear cells. Some reviews on non-hepatic diseases associated with HCV infection. pancreas.. Detail of the test used not available. links to the various extrahepatic manifestations remain to be proved. however. 2001 Ferreiro et al. oral mucosa. kidney. 1997. 2000c). and spleen.. However. 1996 Taliani et al. 1999 Cacoub et al.

. Notably. although we have 1992. 1995 109 France European 3 from 3 to 75% using second-generation Boscagli et al. 1999. frequently not dependent on the HCV genotype.. lymphocytic infiltration in HCV-infected patients was pericapillary rather than periductal. (1986).. e 1999. hepatitis C patients are histologic or serologic abnormality. Guisset et al.. 1999 98 Spain European 7d using a RIBA-2 technique) has been reported Szodoray et al. since this lesion was found represented by histological signs of mild sialadenitis. Other absent (but may be underevaluated) (Table 2). 1996 18 UK European 0d antibodies in SS primary patients ranging Wattiaux et al.. 1996. 1994. 1999 53 Sweden Copenhagen 2 Conversely.. 1994a).. lymphoma.-globulinemia Barrier et al. and that lymphocytic capillaritis resembled an early stage of disease (Pawlotsky HCV-infected patients may frequently have Sjögren-like et al. Pawlotsky et al. Verbaan et al.. False-positive Loustaud-Ratti et al. Vitali et al. 1993 22 France Na 9 (frequently observed in SS) is present (Marson Vidal et al. Loustaud-Ratti et al. no specific antinuclear (SS-A [anti-RO] and SS-B [antisaliva are more likely to complain of xerostomia (Roy et al. the European-prothan those fulfilling the Fox criteria. 1994).. Pirisi et al.. 1995 100 USA Fox IIe 1 European (mainly Italian and Spanish) Masaki and Hayashi.. 1992 22 Greece Vitali 5 the inclusion criteria (Table 3). Several studies data confirm the lack of relationship between the presence of seem indeed to indicate that this sialadenitis may be signifisialadenitis and particular genotypes (Loustaud-Ratti et al. 1994a. cantly different from that of SS. Much of the work on HCV-ve+a Reference n Country Criteria (%) sialadenitis in HCV infection is not from dental institutions.. whereas in patients infected with each of the three main HCV serotypes clinical evidence of dry mouth and mainly of dry eyes is often present in developed countries (Pawlotsky et al. d ELISA only. 1993 20 France Fox I 10 been reported when hyper. Scott et al.. who reported that the prevalence of SS trative disease. 1999 90 Spain European 14 eration confirmatory immunoblot assay Coll et al. considered as distinct from SS (Roy and Bagg. tion.. the HCV test used. respectively. from 14 to 19% using third-generation Jorgensen et al.. sarcoidosis. Coates et al... 1998).. a RIBA confirmed. with no CONTROVERSY #1 destruction of the salivary gland (SG) ducts. Haddad et al. Marrone et al. 1996 23 France Na 5d ELISA.. milder histopathology (with a CD8+ rather than a CD4+ virus in the saliva (Ferreiro et al. 2001. 1995.. 1992 26 Italy Fox I 0 HCV-infected. 2001 213 Hungary European 6 in USA and UK studies (King et al. Further data (Almasio et al. 1991. ing diseases such as hepatitis C. Boscagli et al. 2000) (Table 3). 1994 26 Italy Na 4 matory tests are clearly recommended so that King et al. 1992).. and in the posed (including Vitali and Copenhagen) criteria can be fulfilled without a requirement for latter classification. Taliani et al.. Porter et al... 2002). Ferreiro et al. 1992). and thus there are few availFerri et al. the number of patients fulfilling the b Not available. The last Fox classification excludes patients with a history of pre-existhas been highlighted by Laustaud-Ratti et al. 1997 26 Spain European 19d (RIBA) (Ramos-Casals et al... 1996 62 France European 19 ELISA. few data on lachrymal and salivary function in these patients. 1997). lower HCV prevalence (0-1% Selva-O'Callaghan et al.. There is no female predomi2001).. In contrast. 1994b). De Bandt. 2000. 1994a. Indeed. Cacoub et al. and fewer clinical symptoms (Pawlotsky et al. the frequency varying with the Vitali et al. 14(2):115-127 (2003) Crit Rev Oral Biol Med 117 . 1995 98 Japan Na 11d authors have reported prevalence of HCV Porter et al.. 1968. 1991 20 Italy Nab 5 able data on the prevalence and effect of Marson et al. T-cell predominance). or other causes of lymphocytic infil(2001).. 1992 26 France Na 8 immunoenzymatic (ELISA) HCV tests have Mariette et al. 2000.. (III) Pathogenesis of HCV-related Sialadenitis Henderson et al. 1991 20 Italy Fox Ic 0 hyposalivation in such patients. 2001)... 1994 44 USA Na 0 bias can be avoided. a less frequent association with the HLA-DR3 but whole salivary flow is not associated with the presence of the allele. Poet et al. 1994 28 France Fox I 14d et al.... 1993. 1997 31 Spain European 10 Fernandez-Campillo et al. It has been reported that patients with HCV-RNA in the nance. Verbaan et al. 1992 20 France Na 10 from 0 to 19% of patients with frank SS can be Aceti et al....... and Vitali et al. 1996). 1997. This problem Fox and Saito (1994). 1994. 1992. HCV may be present in the saliva of 83% of patients with HCV-associated sialadenitis TABLE 3 (Jorgensen et al.... Fox et al. in contrast to SS.. 1994. Haddad et al. 1992 44 Italy Vitali 5 geographical region. European criteria is five.. 1999. LA]) antibodies.. 2001. A subsequent study noted that. and thus confirFrisoni et al.. 1996) and is also detectable in Association of HCV Infection with Sjögren's Syndrome tears in concentrations higher than serum (Feucht et al. In contrast to the Fox (San Diego) classification system... and from 5 to 19% using second-genGarcia-Carrasco et al. 1994.. sialadenitis with mild clinical symptoms.in a cohort of 45 French HCV-infected patients increased from or 4 sialadenitis (according to Chisholm and Mason's classifica8% to 38% according to the Fox and the European criteria. VIRAL FACTORS 2002) have shown that up to 80% of HCV-infected individuals An early study suggested that the presence of sialadenitis was may have some salivary or lachrymal abnormality..to ten-fold greater c Fox et al. several Marrone et al.. Pirisi et al.

The model also predicts that xerophthalmia.7 13.7 NA 3. 1974). but it seems unlikely to be induced by an immune reaction against ductal cells expressing viral antigens.. HCV is uncommon in SS patients without mixed cryoglobulinemia (King et al.. which are able to infect the salivary glands of their arthropod vector. et al. Verbaan et al. 2001). 1982 Rebora and Rongioletti. 1994 a b c d e f Country Italy Italy USA Denmark USA USA UK UK Italy Italy Spain Italy Italy UK Spain Study Group 37LPb 44LPb 389LPb 54OLP 73LPb 15OLP 55LPb 113OLP 21OLP 62LPe 65OLPb 577LP 96OLP 180OLP 187OLP Cirrhosis (%) 1... However. 1991).5 9. 2001). since only one out of 20 transgenic mice showed a weak antibody reaction to E1 protein. rarely reported in HCV-infected patients. 1995. 1974). closely resembling the Chisholm and Mason grade 3 or 4 sialadenitis noted in humans (Haddad et al. or of polyclonal IgG and IgM (type III) (Brouet et al. 1988 del Olmo et al..1 38....3 3. 1999).5 10.CRYOGLOBULINEMIA The term 'cryoglobulinemia' refers to several syndromes characterized by the presence of abnormal proteins (cryoglobulins) that precipitate from cooled serum (Brouet et al. whereas 80 to 100% have HCV infection (Dammacco et al. 2001).7 0. would be a late development.7 12e 13... HCV antigens have been immunohistochemically detected in SG epithelial cells (De Vita et al.52 5.5 33..0 NA NA 52.. Significantly different from the control groups.1 100 17... According to the composition of the cryoprecipitates. 2001).8 21. 1992a el-Kabir et al.2 - Including abnormal liver function tests.9 25.or interleukin 2 by HCV proteins or the induction of an immunological disturbance by the transgene. 1984 Korkij et al.87 7.6 0.and negative-strand HCV-RNA has been detected in minor SGs of patients with sialadenitis and chronic hepatitis C by PCR and in situ hybridization (Takamatsu et al. 1984d Katz and Pisanti. This model clearly suggests a direct role of the viral proteins in the pathogenesis of HCV-related sialadenitis. Nests of lymphatic infiltrates were also noted in the LGs... 1980).5 11. About 15% of patients with MC have SS (Gorevic et al. not all the HCV-positive patients with evidence of salivary gland abnormalities have detectable serum cryoglobulinemia (Pawlotsky et al.. 1997). an animal model of transgenic mice carrying the HCV envelope genes E1 and E2 has been constructed (Koike et al. 1985 Monk. because lymphocytic capillaritis preceded sialadenitis. and Chronic Liver Disease Chronic Erosive LP (%) Hepatitis (%) NAc NA NA 70. However. it became evident that cryoglobulinemia is the most frequent extrahepatic manifestation of the virus (Dammacco et al. 1999). The pathogenesis of this sialadenitis in transgenic mice is unclear... 1993d Bagan et al..7 4. After the identification of HCV..3 NA 4. primary biliary cirrhosis and liver lymphoma). positive. 1997). other liver diseases (e. 1990d Gandolfo et al.0 NA NA 9.g. TRANSGENIC ANIMAL MODEL Recently. cryoprecipitates are composed of polyclonal IgGs against HCV and monoclonal IgM rheumatoid factors (type II).0 25.3 7. The mice developed an exocrinopathy involving the SGs and lachrymal glands (LGs) in 84% of cases. Biasi TABLE 4 Studies on the Possible Association among Lichen Planus (LP). 1985 Ayala et al. Precise characteristics of LP not stated. 2001). 1990 GISED.. 1994a. both these cryoglobulinemias are designated as mixed cryoglobulinemia (MC)..5 11. Initially. Whereas SGs of patients with chronic HCV infection but without clinical and histological signs of sialadenitis were not infected (Taliani et al. Case-control studies. 1985 Scully et al. 1992. and the infected cells did not show any differences with respect to unaffected ones (Arrieta et al.3 42.3 14. Moreover. Loustaud-Ratti et al.7 NA 100 NA 22. No significant difference from the control groups. abnormal liver scan. 1992).3 3.. In particular.0f 21.. In most HCV patients. 1995) but not invariably (Verbaan et al. 118 Crit Rev Oral Biol Med 14(2):115-127 (2003) .9 61. DIRECT INFECTION OF SALIVARY GLANDS HCV is distantly related to flaviviruses (Houghton et al.. but soon focal infiltrates of small lymphocytes appeared.6 7. 1984 Powell et al. Not available. HCV seems to infect and replicate in epithelial cells of the SG acini.8 33. this may reflect the pathological sequence in Sjögren-like sialadenitis occurring in human patients. but they occurred later and were less extensive than those found in the SGs. there is no correlation between the percentage of infected SG epithelial cells and the serum HCV-RNA titer.2 7. 1994. 1984 Mobacken et al. Alternative explanations include the induction of interferon. Arrieta et al.4e 24... Oral Lichen Planus (OLP).3 1... 1986 Cottoni et al.2 Liver Abnormalities Overall (%)a 13.4 Reference Rebora et al.. pericapillary lymphocytes were found.

.. and 22 (40.8 44 20 23 0 0 0 23 13. In a minority of patients.. 1995 Sanchez-Perez et al.. 1998 Rossi and Colasanto.4d 3.8 55 17 45 0 0 6. Only 19 patients were tested.9 20...2 NA NA NA 34. 2002 Ilter et al. Probably..7c 10c 1. or superantigens. 1995a Tanei et al. 1998 Divano et al.3d 3d 3d 6.. 2000).4d NA NA 1. 1994 Gandolfo et al. chronic.. 1996 Serpico et al. 2001 Ibrahim et al. 1994 Schmitt et al. 1992 Rebora.5c 1... Six (22%) with oral lichen planus and 21 (78%) with lichenoid reactions.2 14 23 9. persisting for more than 20 years without spontaneous remission (Scully et al. 2000 Not available.. 2001 Eisen. Significantly different from the control groups. and recalcitrant than the cutaneous type.9%) had cutaneous. 1998 Kirtak et al.8 4.1f 32 28.. 1997 Mignogna et al.... OLP is unlikely to be caused by a single antigen.9 8. Eleven (20. 14(2):115-127 (2003) Crit Rev Oral Biol Med 119 .. 1998 Ingafou et al.... 1999 Figueiredo et al.1d 8 4.. (IV) Lichen Planus Lichen planus (LP) is a chronic inflammatory disease that affects skin and mucous membranes of squamous cell origin. 1999 Beaird et al. 1999 Roy et al. 2002 Van der Meij and van der Waal.CONTROVERSY #2 Analysis of experimental data suggests that HCV proteins play a direct role in the pathogenesis of sialadenitis.. 1997). OLP is the common outcome of the influence of a limited range of extrinsic antigens. precipitating factors have been identified. No significant difference from the control groups. 2000 Erkek et al. 2000 Nagao et al. Only patients with severe liver disease were tested. 1996 Bagan et al. 1997 Chuang et al. 2000 Bellman et al.7 21.. Prevalence data taken from the general population of São Paulo.7%) had mucocutaneous lichen planus.4d 5d 0c 3c 4. four genital).8 13 62 37. The oral form of LP (OLP) seems more common.7 27. 1995 Egan and Zone. given that studies of T-cell receptor variable region genes from lesional OLP T-cells have not revealed the use of a restricted number of different variable region genes (Thomas et al. 1997 Grote et al. 21 (38.8 12. 1995 Carrozzo et al..9 29 16 4.4%) of the 54 patients had mucosal (seven oral.1d NA NA NA NA NA NA 2.e 32 70b 100b 263b 100b 45b 45 25 78 100b 55b 45 27g 30 29b 22 24 31b 195b 72 73 54h 43 68b 55b Controls (n) 112 306 87 100 70 100 100 45 18 82 100 110 32 41 40 20 75 73 54 30 1059i - France Germany Italy Japan Spain UK USA Turkey Egypt Brasil Netherlands a b c d e f g h i Cribier et al. All oral LP. These include dental materials (mainly dental restorative TABLE 5 Prevalence of Hepatitis C Virus Infection in Patients Affected by Lichen Planus Country Reference Study Group HCV+ve HCV-RNA (%) (%) 3.4 NA NA NA 60 NA NA 16 NA NA NA 0 16 NA NA NA NA NA NA NA 9.4d NA NA NA NA NA NA NA NA NA NA NA - LP (n) 52 102b 28b 83 24b 46 56 105b. altered self-antigens. 2001 Chainani-Woo et al. 1994 Dupin et al. 1998 Imhof et al.6c 4.... 1995 Gimenez-Arnau et al..7d 5d 2.8 0 NAa NA 18 14 4. 1997 Dupond et al. although it seems unlikely that sialadenitis is induced by direct infection of salivary glands or by an immune reaction against ductal cells expressing viral antigens.8d 25d 5d 0c 1.5 34.3 NA NA 0 Control Group HCV+ve HCV RNA (%) (%) 2. 1998 Tucker and Coulson.

Erkek et al.. 2001).. 1996. 1996.... and it appears to be uncommon in the UK (Harris et al... drugs (such as non-steroidal antiinflammatory drugs and angiotensin-converting enzyme inhibitors). Markers of past hepatitis B virus (HBV) infection (antibodies to hepatitis B surface antigen [HBsAb] and to hepatitis B core antigen [HBcAbIgG]) have been reported in 21 to 30% of Spanish and Italian patients having LP (Ayala et al... 1994.. 1996a). Tucker and Coulson. 1995. 1997. 1997. 14(2):115-127 (2003) 120 Crit Rev Oral Biol Med .and B-cells among infiltrating lymphocytes regardless of the presence or absence of HCV infection (Kirby et al. Carrozzo et al. Grote et al. Chuang et al. 1994. sex.8 to 4. 2000) and have suggested that HCV could be involved in the development of LP. but this prevalence is near the average figure in the Mediterranean area. whereas the association of LP with primary biliary cirrhosis is mostly due to the administration of penicillamine treatment (Graham-Brown et al.. especially in Mediterranean patients with oral erosive LP (Gandolfo et al. Oleaga et al. Schissel and Elston. Gandolfo et al. Agner et al. Hyrailles et al..6 to 20% of patients with HCV-related chronic hepatic disease may have LP (Pawlotsky et al.. 1993. Nagao et al.. but a recent controlled study reported that the reticular and plaque clinical forms are prevalent as well (Mignogna et al. 1994.. and alpha-1-antitrypsin deficiency have rarely been related to LP (Rebora. 1994. Divano et al. 1994.. Daoud et al. Carrozzo et al. Calista and Landi. 1998.. 1992b). though mainly genotype 1b seems associated with LP. 1996. Spain. Benchikhi et al. since 1991. 1998). 1995. Analyses of early data suggested that mainly oral erosive OLP may be linked to HCV infection (Gandolfo et al.. and infectious agents (including herpes simplex virus I. 2001). Jauregui et al. On the other hand. 1993... especially the oral variety (Table 5). herpes virus 6.. since 7. Beaird et al.. Cayla et al. 1986.. 2000. In contrast to the Mediterranean data. 1992.. Bagan et al. 1995.. 1998. Lodi et al. 1997a. 1996). 1985. mainly of the oral cavity. Moreover. 2001). 1994. 1999).. 1982. OLP would probably be more easily identified in HCV-infected patients in countries with low levels of HCV. 1995. Roy et al. 1994). 2000.. 2001.. 1995)... Carrozzo et al. Japan.... Several controlled experiments have confirmed that HCV is the main correlate of liver disease in patients with LP (Carrozzo et al. this difference seems only partially related to the level of endemism of HCV in the general population.. 2001. 1995) was probably influenced by the prevalence of HCV in the general population. 1998. 1998. Kirtak et al. Apparently. whereas a study from southern France (Nice) reported 29% of HCV-positives in 28 patients with erosive OLP (Dupond et al. are clearly needed. HCV-associated hepatic disease may precede LP onset or may be diagnosed together with it. 1997b). 1997.. 1994. 1992. Henderson et al.. and Helicobacter pylori and hepatitis viruses) (Scully et al. 1991. whereas investigations in England and Holland (Ingafou et al. (V) Pathogenesis of HCV-related LP (A) VIRAL FACTORS The role of particular HCV genotypes in the pathogenesis of HCV-related OLP is ruled out by the observation that LP can be associated world-wide with the same genotypes commonly found in patients without LP (Pawlotsky et al. there are no significant differences in the histopathological characteristics specific to OLP or in the ratio of T. 2000).. 1984... CONTROVERSY #3 LP. 1993. Nevertheless. Jubert et al... Almost all data from Italy.. Bez et al. 1998. 1998... hepatitis G virus and TTV. 1995. Tanei et al. However. There are also controversial data from Germany and Turkey (Imhof et al.. 1995. 1996. 2000. On the other hand.... Gimenez-Arnau et al. retrospective and prospective studies of Scandinavian and British OLP patients have failed to show any significant correlation with liver diseases (Mobacken et al.9% in their sixth decade were HCV-infected (Hayashi et al. 2000b. 2000a). Schmitt et al. Figueiredo et al. Scully et al. Dupin et al... but no hypothetical pathogenic correlation could be found until sensitive hepatitis C virus (HCV) assays became available. 1997). Eisen. the majority of patients with both LP and CLD are not HBV-infected (del Olmo et al. 1982.. a smallscale study from Egypt.. Mouly et al. 1994. Curiously.. haemochromatosis. Grote et al. Tanei et al. the picture appears quite complicated: Low prevalence of HCV infection ranging from 3. are not associated with LP (Pedersen. cytomegalovirus.9% was found in OLP patients from northern France (Strasbourg) and Ile-de-France (Paris) (Cribier et al.materials such as amalgam). 1999). 1995a... 1998. did not report a significant association between LP and HCV (Ibrahim et al. possibly reflecting the low incidence in those populations. Brazil. 2001). 1998. The frequent association of LP with chronic liver disease (CLD) is well-known (Table 4). Amichai et al. However. The risk of chronic liver disorders in LP patients is in fact independent of age.. el-Kabir et al. Well-designed prospective studies.. 1995.. Epstein-Barr virus and the recently discovered viruses. Nagao et al. and all but one study in the USA support the existence of a relationship between LP and HCV infection (Divano et al. stress. Dupin et al. 1990). There are also a few reports of mainly skin lichenoid eruption following administration of different HBV vaccines (Rebora et al. such as the UK (Carrozzo.. 1999). Rodriguez-Inigo et al. mainly those coming from southern regions (Kyushu) (Nagao et al.. 1992. the very high prevalence of HCV infection among Japanese LP patients (38 to 62%). mainly from countries with low prevalence of HCV infection. Coates et al. Nagao et al. 1990. trauma.. Mignogna et al. 2000. Rossi and Colasanto. Ilter et al. Powell et al... Tanei et al. Strumia et al. Bellman et al. 1997.. 2001. 1990. 1994. Sanchez-Perez et al. In France. Chainani-Wu et al.. Lodi et al. more than 80 case reports worldwide have supported the link between LP and HCV infection (Mokni et al. Because these prevalences are generally higher than expected. 1996. Serpico et al. and alcohol consumption.. 2002. Carrozzo et al. 1994. 1994a.. 1992).. 1995a. Epstein-Barr virus. and is still significantly high after adjustment for a positive hepatitis B surface antigen (HBsAg) reaction (GISED.. Wilson's disease. 1999.... 1996). 2000). 1993). 2000. 1996. van der Meij and van der Waal. Pellicano et al. The few studies investigating the frequency of LP among HVC-positive subjects showed that from 1.. 2000.. Sassigneux et al. Studies have also shown no differences in serum levels or HCV-RNA levels between HCV-infected patients with LP and those without (Nagao et al. del Olmo JA et al.. Toure et al. 2001)... appears to be significantly associated with HCV infection in southern Europe and Japan but not in Northern Europe. Bellman et al.. del Olmo et al. which has the highest reported prevalence of HCV infection in the general population. 2000) did not find HCV antibodies in LP cases. Rebora. 1998. 2001.. Gandolfo et al.. 1996). 2002.. Rebora. 1999. Nagao et al.. human papilloma virus... 1995b.. Cecchi et al. 2002). Mignogna et al.

to ameliorate (Doutre et al. In any case. 1997. in vivo. 2001).. In situ and peripheral blood-derived T-cell lines were able to proliferate and to produce gamma interferon upon stimulation with structural and non-structural HCV antigens. 1995.. 1998).. 1996b.. 2002).. 1999. Sassigneux et al. Cayla et al. most OLP-HCV+ve cases do not have this type of auto-antibody (Carrozzo et al.. Perreard et al. The lympho-mononuclear infiltrate typically found in oral lichen lesions rather suggests that the progressive destruction of the oral mucosa lining is due to local immune aggression. mainly in cases with oral involvement (Agner et al. 1998). 2000. Tcell clones present in the oral mucosa showed a TCR-V chain usage different from those circulating in the peripheral blood. 1995a).. 1999). although anti-epithelial antibodies have been detected with significantly higher frequency in patients with HCV-related OLP than in those without HCV infection (Lodi et al. Both in situ hybridization and extractive PCR techniques revealed the presence of replicative intermediate HCVRNA in OLP specimens (Arrieta et al. whereas secondary LP as well as OLP is not. at least in Italy.) for more than 6 months (Lodi et al.. 2002). porphyria cutanea tarda (PCT). HCV-related OLP appears to be associated with the HLA-DR6 allele in Italy (Carrozzo et al. Mariette. all but two of the samples studied were from persons not infected with HCV. Lymphomas occurring in both diseases share several characteristics: predominance of low-grade. 1997a). Lodi et al. 1995. Nagao et al. 1995). and their pathological significance is probably negligible in the absence of -IFN therapy. Moreover. 2000c... of chronic HCV infection (Ferri et al.for a period of 12 months can induce anti-epidermal auto-antibodies.. 1997a. Oral verrucous and squamous cell carcinomas have been reported in HCV-infected patients with or without OLP (Nagao (D) DIRECT INFECTION OF LP LESIONS There are few data on the localization of HCV antigens in LP. the effect of -IFN therapy for HCV infection in patients with LP differs markedly from case to case. it has been reported that PCT susceptibility is different in British and Italian patients. Analysis of experimental data strongly suggests that HCV is involved in the pathogenesis of OLP via local induction of an immune response specific for HCV epitopes. 1994. 1993.. This does not seem to be caused by an elevated frequency of non-organ-specific autoantibodies (Carrozzo et al... However. 2000c. Erkek et al. 1997a). Nagao et al... 2001). 2002). Carrozzo et al.. 62% of the OLP-HCV+ve patients with circulating anti-epithelial auto-antibodies had been treated with alpha interferon (IFN... 1997).(B) MOLECULAR MIMICRY A constant feature in LP patients with HCV infection is the presence of polyclonal hypergammaglobulinemia (Carrozzo et al.. marginal zone histological type. 1999). Nunez et al. 1993.. 1991. Fornaciari et al. often of a lichenoid type (Sookoian et al. 1997... geographic heterogeneity in the prevalence of HCV infection similar to that observed in OLP patients was also found in patients with other extrahepatic abnormalities linked to HCV infection... Hildebrand et al.. the USA. analysis of some data suggests that OLP lesions may contain both genomic and antigenomic HCV-RNA (Arrieta et al. and hypergammaglobulinemia should rather be linked to cryoglobulinemia (Carrozzo et al. in both diseases.. The occurrence of B-cell non-Hodgkin's lymphoma is a complication of SS and. (1996) have shown. frequency of mucosal localization. 1997b). 1998). and showed the same specificity. Protzer et al. However. Lamoril et al... 2000. neous LP. Guijarro et al.. Carrozzo et al.. 2001). For unknown reasons.. McColl et al. 1995. In this study.. Nagao et al. being correlated with mutation in the human leukocyte antigen (HLA)linked hemochromatosis gene C 282Y in the former and to the H63D gene and HCV in the latter (Elder and Worwood. 1996.. 1995.. Zuckerman et al. This striking fact suggests the existence of possible genetic differences among different populations... 1997.. 2001). 1998. Furthermore. 2001).. Indeed. 2000c. sequence analysis suggests a possible compartmentalization of HCV in the oral mucosa (Carrozzo et al. Areias et al. 1996.. (C) GENETIC FACTORS Interestingly.. Luppi et al.. Papini et al. such as serum autoantibodies. The adjuvant use of ribavirin with -IFN also seems to increase the risk of adverse cutaneous reactions. 1999). Using sensitive extractive PCR. mainly associated with type II cryoglobulinemia or SS. 1999.. 1992.. or to trigger or worsen LP lesions. 1998. Ascoli et al.. 2001). Carrozzo et al. CONTROVERSY #4 Immunogenetic factors partially explain the geographic heterogeneity of the association between HCV and LP. that low-dose IFN.. Indeed. 1996. tetramer assays with four different HCV antigens showed that the frequency of HCV-specific CD8+ T-cells was higher in mucosa tissue than in the blood (Pilli et al. 1996.. whereas data on any effect on the oral mucosa are still lacking... however. Varela et al. d'Agay-Abensour et al... Barreca et al. investigators detected positive and negative strands in 82 to 93% and 21 to 36% of the OLP tissue specimens. 1999). It has been proposed that. 1994. Two studies used various immunohistochemical techniques to look for HCV antigens in paraffin-embedded sections of cuta14(2):115-127 (2003) Crit Rev Oral Biol Med 121 . the first event of lymphomagenesis is chronic stimulation at the site of the disease of polyclonal B-cells capable of secreting rheumatoid factor (De Vita et al. Heintges et al. association with asymptomatic low-level cryoglobulinemia (De Vita et al. 1994. 1995) or formalin-fixed (Boyd et al. 2001). 1998). Dalekos et al. However. 2002). but all samples failed to take up the stain. molecular mimicry between the virus and host epitopes is unlikely to be active in LP. and this could partially explain the peculiar geographic heterogeneity of the association between HCV and LP. possible transformation into a large Bcell lymphoma. Recent data have shown that HCV-specific T-cells can be found in the oral mucosa of patients with chronic hepatitis C and LP (Pilli et al. Strumia et al. Luppi et al. (VI) Other Diseases Some cases of parotid gland lymphoma in Italian patients with HCV infection have been reported (De Vita et al. 2000.. either frozen (Sansonno et al. Schlesinger et al. ManjónHaces et al. and lymphoma (Lenzi et al.. 2000).. HCV is probably unlikely to cause direct damage to epithelial cells in OLP lesions.. 1995. 1993. since it was also found in normal mucosa (Arrieta et al. 1996.. 2001). and Japan.. Pedersen. 1993. and Fleishmann et al.. 1992... Nagao et al. whereas no HCV intermediate RNA was detected in skin specimens of LP. although HCV-RNA may be occasionally detected in lesional skin (Mangia et al. -IFN has been reported to have no influence (Pawlotsky et al. 1997. Most idiopathic LP is related worldwide to the HLA-DR1 (DRB1*0101) allele (La Nasa et al. 1992.. Nagao et al. 1994. Mariette. respectively (Nagao et al. Conversely.

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