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EDITORIAL
Hepat Mon 2010; 10(3): 161-164
Hepatitis C Virus and Lichen Planus: The Real Association
Nima Mahboobi 1, Farzaneh Agha-Hosseini 2, Kamran Bagheri Lankarani 3
1 Department of Oral and Maxillofacial Surgery, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
nima.mahboobi@gmail.com
2 Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
aghahose@sina.tums.ac.ir
3 Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
lankarani@mohme.gov.ir
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Lichen planus (LP) is a common T-cell-mediated chronic inflammatory disease of the stratified squamous epithelium, with unknown etiology. It can affect oral mucosa, the skin, genitalia, hair follicles, nails, esophagus, urinary tract, nasal mucosa, larynx and even the eyes (1).
Local conditions such as poor oral hygiene and smoking may increase the chance of the immune trigger by increasing the exposure. Oral LP (OLP) affects women more than men (1,2) and occurs predominantly in adulthood, although young people and children might be affected (1).
Clinically, the OLP has six variants: Papular, reticular, plaque-like, atrophic, erosive and bullous. These features may occur individually or in combination (2). There is ongoing concern that OLP may be premalignant While skin lesions occur in 20% of patients with OLP, cutaneous lesions are associated with oral lesions in 70%–77% of cases (4). The oral mucosa in OLP is highly accessible for an accurate examination. Therefore, OLP is ideal for the study of human T-cell-mediated inflammation and autoimmunity (5-7). Oral lesions are characteristically raised multiform white lesions, accompanied by areas of erosions and pigmentation (1). Histological features of the LP are nonspecific and there are no well-accepted criteria for its diagnosis (8) which makes its definite diagnosis difficult.
Hepatitis C virus (HCV) is a single-stranded RNA virus which is recognized as a global concern (9). Worldwide, more than 170 million people are infected with HCV (10). The virus has an extremely variable genome, six distinct genotypes and multiple subtypes (5). It is estimated that 0.16% of the Iranian general population are infected with the virus (11). Infection with HCV has been found to be a major cause of liver diseases. Although the incidence of HCV infection is significantly lower than that of hepatitis B virus (HBV) infection, the rate of chronically infected individuals is much higher (12).
Morbidity associated with HCV infection is not only due to the sequelae of chronic liver disease, but is also due to a variety of extrahepatic manifestations (5). There is no efficient vaccine available and it seems too optimistic to predict one in the near future. More epidemiologic studies are needed to better assess the epidemiological characteristic of the disease (13).
Correlation between HCV infection and some oral diseases such as OLP, Sjögren’s syndrome, and sialadenitis has been reported. Moreover, OLP was found associated with a number of viral infections including Epstein-Barr virus, cytomegalovirus, varicella zoster virus, human herpes virus , human papilloma virus, and human immunodeficiency virus (HIV). However, the most frequent evidence relates to HCV infection (14, 15).
If this would be a true association, OLP in certain populations may be used as a sign of HCV infection in asymptomatic patients, leading to early diagnosis and treatment, and possibly a better prognosis of the infected patients (5, 14, 16).
The first description of this association was reported in 1991, just two years after discovery of HCV (17). During the past years, studies from Taiwan (18), Brazil (19), Israel (20), Saudi Arabia (21), Turkey (22), Iran (23) and Thailand (24) showed statistically significant correlation between presence of LP and HCV infection. A study from Japan reported that the prevalence of OLP increased as the subjects grew older (25). On the other hand, many researchers found no correlation between chronic HCV infection and LP. An Italian study showed just a weak relation between HCV infection and OLP (26). Another two Italian studies (27, 28), two Indian studies (29, 30) two Iranian studies (31, 32), one Brazilian study (33), one Turkish study (34), one Serbian study (35) and one from UK (36) were not able to find any correlation between chronic HCV infection and LP. A recent meta-analysis exploring the association between HCV and LP, nonetheless, revealed an important association. The pooled odds ratio point estimate of the prevalence of HCV infection among patients with LP was 5.4 (95% confidence interval [CI]: 3.5–8.3), compared to the control subjects. The odds ratio for LP among patients with HCV compared to control participants was 2.5 (95% CI: 2.0–3.1) (37).
The most likely hypothesis describing the association of HCV infection and LP is regional based correlation (37, 38). Nevertheless, it seems very superficial to just conclude a simple geographical correlation. This non-homogeneity in results from different geographic areas may have several reasons. Many of these reports for LP come from registries of hospitals or university affiliated clinics. These cannot represent the real situation in the general population for sure. Difficulties in making a definite diagnosis for LP—as previously mentioned—make interpretation even more complex. Estimation of the point prevalence of HCV infection in the general population in these regions and how well the control group was selected are other contributing variables which may lead to divergent results. Also, as HCV treatment, especially interferon-α, may provoke oral lesions similar to OLP (39), lack of information on the treatment status of enrollees with HCV infection in many of these studies makes summarizing the results challenging (37).
Analysis of available data revealed that it is too premature to reach a definite conclusion.
So far, the most plausible path for this association is based on various factors such as region. Furthermore, we need to find the underlying mechanisms for the association. Experimental data strongly suggest that HCV is involved in the pathogenesis of OLP through local induction of an immune response specific for HCV epitopes (5). HCV RNA has been detected both in sera and in oral lesions of patients with OLP; however no direct pathogenic effect of HCV on oral mucosa could be demonstrated (40-42).
Theoretically, epitopic similarities between HCV and keratinocytes could explain the association between LP and HCV, but this could not be demonstrated in any studies. It is believed that this association might be related to cytotoxic immune response to epithelia cells infected with HCV (41, 43). In some of these reports, HCV infected patients with LP had a higher serum transaminase level, and a higher chance of being diabetic than those without LP (37, 44). On the other hand, oral lesions in patients with HCV infection with LP were more likely to be erosive, when compared to non-infected LP patients (45-47). This may reflect a synergistic effect between the two conditions. Interestingly, co-infection with HIV decreases the possibility of LP in HCV-infected patients, probably through an immunodeficiency state (48, 49). It should be mentioned that no correlation was observed between the viral load and HCV genotype and the likelihood of developing LP in HCV-infected patients (50-52).
Overall, it can be concluded that HCV-infected patients may have increased risk of developing LP or alternatively, patients with LP may be at a higher risk for developing HCV infection (38). Altogether, screening OLP patients for antibodies to HCV is recommended (20). More prospective well-designed studies (especially cohorts) are necessary to clarify the above issue.
There are some reports of association between LP and other chronic liver diseases including primary biliary cirrhosis, and cirrhosis of unknown origin. This may indicate other modes of interaction.
Why is this association important?
As HCV infection is usually indolent so that patients may present only in late stages of the disease with serious complications like cirrhosis and chronic liver disease, screening of patients with LP may help in early diagnosis of the HCV infection in a subset of patients. Early diagnosis, education and awareness of these patients may decrease risk of transmission to others. In a cost-effectiveness analysis, screening of patients with LP with ELISA was found cost-effective only with the presence of other risk factors such as history of intravenous drug abuse (IVDU), sex with IVDU , or history of transfusion (53, 54). Hepatitis Monthly, Summer 2010; 10(3): 161-164 Nima Mahboobi et al. 163
Reviewing these findings may help us in better understanding the pathogenesis of HCV infection, especially its extrahepatic manifestations. It should be emphasized that the epidemiologic studies could not prove any causative role for HCV in LP.
References
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Association between hepatitis C virus and oral lichen planus
Authors:
Oliveira Alves MG
University of Estadual Paulista, São José dos Campos Dental School, Department of Biosciences and Oral Diagnosis, São José dos Campos, São Paulo, Brazi
Almeida JD
University of Estadual Paulista, São José dos Campos Dental School, Department of Biosciences and Oral Diagnosis, São José dos Campos, São Paulo, Brazil
Guimarães Cabral LA
University of Estadual Paulista, São José dos Campos Dental School, Department of Biosciences and Oral Diagnosis, São Paulo, Brazil
Manuscript:
Please cite this paper as:
Oliveira Alves MG, Almeida JD, Cabral LAG. Association between hepatitis C virus and oral lichen planus. Hepat Mon. 2011;11(2):132-133.
Article history:
Received: 12 Sep 2010
Revised: 09 Nov 2010
Accepted: 11 Nov 2010
Keywords: Lichen planus; Hepatitis C virus
2011 Kowsar M.P.Co. All rights reserved.
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Dear Editor,
We read with great interest the article, "Hepatitis C virus and Lichen Planus: The real association" by Mahboobi et al. (1) because our practice serves a large group of patients with Oral Lichen Planus (OLP). OLP has been associated with chronic liver diseases, particularly those that have Hepatitis C Virus (HCV) (2) as a possible etiology. The association between HCV and Lichen Planus has been described in the literature, especially among patients of Mediterranean origin, but is not generally observed in patients from Northern Europe, indicating a strong geographic relationship (2). Carrozzo et al. (2) reported that HCV-associated Lichen Planus appears to be a distinct subset among Lichen Planus conditions and is particularly associated with the HLA class II allele, HLA-DR6. This fact may explain in part the peculiar geographic heterogeneity seen in HCV-associated Lichen Planus. Given that HCV infection can be asymptomatic, screening patients with Lichen Planus for this virus is important because it permits an early diagnosis and a better prognosis.
Therefore, we request serological tests for patients diagnosed with OLP and encourage this practice. At our practice, none of the patients diagnosed with OLP have been HCV positive (3). However, the number of patients in our study is not sufficient to demonstrate a positive association, which might be explained by the ethnic diversity of Brazil, although a geographic or ethnic correlation is difficult to establish. The pathogenesis of OLP induced by HCV is uncertain, but two hypotheses have been raised to explain the mechanism of the triggering of OLP by HCV. The first hypothesis suggests that virus replication is associated with the oral epithelium and thus contributes directly to the development of lesions. The second hypothesis proposes that the high mutation rate of the virus results in repeated activation of immune cells, increasing the probability of crossreaction with its own tissue and, consequently, the risk of autoimmune disease. In certain genotypes, crossreactivity that activates immune cells against epithelial cells is favored (4). According to Arrieta et al. (5),
HCV infection is not a direct causal factor of OLP because replication of HCV was observed in both mucosa with and without OLP. In addition, the authors found a mononuclear cell infiltrate around the epithelial cells of HCV-seropositive patients with and without OLP. However, the authors did not rule out the possibility of HCV inducing changes in the host that may have led to an autoimmune response. Michele et al. (6) found no clear association between OLP and chronic hepatitis C. These authors postulated that this possible association mainly depends on the frequency of each disease in the population, which would explain the wide geographic variation. However, Del Olmo et al. (7) concluded that HCV plays a role in the etiopathogenesis of chronic liver diseases documented in patients with OLP and that treatment of the disease with IFN-α, which inhibits virus replication, may lead to the development of a lichenoid reaction to this drug.
Despite the controversy in the literature regarding the association between OLP and hepatitis caused by HCV, we partly agree with Mahboobi et al. (1) that screening patients with OLP is of marked importance for the diagnosis of HCV infection given that the latter is usually indolent and can cause serious complications in patients if left untreated.
References:
1. Mahboobi N, Agha-Hosseini F, Lankarani KB. Hepatitis C Virus and Lichen Planus: The Real Association. Hepat Mon. 2010;10(3):161-4. [Hepat Mon]
2. Carrozzo M. Oral diseases associated with hepatitis C virus infection. Part 2: lichen planus and other diseases. Oral Dis. 2008;14(3):217-28. [PubMed]
3. Oliveira Alves MG, Almeida JD, Balducci I, Guimaraes Cabral LA. Oral lichen planus: A retrospective study of 110 Brazilian patients. BMC Res Notes. 2010;3:157. [PubMed]
4. Chainani-Wu N, Lozada-Nur F, Terrault N. Hepatitis C virus and lichen planus: a review. Oral surgery. 2004;98(2):171-83. [Link]
5. Arrieta JJ, Rodriguez-Inigo E, Casqueiro M, et al. Detection of hepatitis C virus replication by In situ hybridization in epithelial cells of anti-hepatitis C virus-positive patients with and without oral lichen planus. Hepatology. 2000;32(1):97-103. [PubMed]
6. Michele G, Carlo L, Mario MC, Giovanni L, Pasquale M, Alessandra M. Hepatitis C virus chronic infection and oral lichen planus: an Italian case-control study. Eur J Gastroenterol Hepatol. 2007;19(8):647-52. [PubMed]
7. del Olmo JA, Pascual I, Bagan JV, et al. Prevalence of hepatitis C virus in patients with lichen planus of the oral cavity and chronic liver disease. Eur J Oral Sci. 2000;108(5):378-82. [PubMed]
HCV and lichen planus
Authors:
Rebora AC7O Clinica Dermatologica dell’Università, University of Genoa, Genoa, Italy
Correspondence:
Alfredo Rebora, Department: C7O Clinica Dermatologica dell’Università, University of GenoaAddress: C7O Clinica Dermatologica dell’Università, Viale Benedetto XV, n.7, 16132City: GenoaCountry: ItalyE-mail: rebdermo@unige.it
Manuscript:
Please cite this paper as: Rebora A. HCV and lichen planus. Hepat Mon. 2011;11(2):134-135.
Article history:Received: 13 Sep 2010Revised: 07 Nov 2010Accepted: 11 Dec 2010
Keywords: Lichen planus; HCV; Hepatitis
2011 Kowsar M.P.Co. All rights reserved.
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Dear Editor,
Mahboobi et al. should be commended for providing a clear and exhaustive review of the literature on the intriguing topic of the association of HCV infection with Lichen Planus (1). It is somewhat surprising, however, especially for a dermatologist such as myself, to read that the histopathology of LP is nonspecific, but for cutaneous LP the specificity is out of question. Actually, the reference that Mahboobi et al. cite for this point concerns oral LP, and most of their statements refer to the oral form of LP. The point is not immaterial, as it was the striking similarity of microscopic LP features with those of the liver affected by HCV-related active hepatitis that should suggest that a connection between the two conditions does exist. In both conditions, a T-cell infiltrate impinges on the cells of the epithelial structure that are in direct contact with the corium: keratinocytes of the basal layer of the epidermis in LP and hepatocytes of the murallium of the hepatic lobe in active hepatitis. Also in both conditions, T-cells induce apoptosis of the epitheliocytes, disorganize the epithelium, and in some instances destroy it (erosive forms).
Some time ago, when I described the first cases of a severe hepatic disease in patients with erosive LP (2), I was amazed not only by the striking similarity, but also by the fact that nobody had noticed it before. Certainly, not all the observations and epidemiological studies concur on the relationship between LP and HCV infection, and the geographical explanation may not be completely convincing. In addition to the explanation provided by Mahoobi et al. the possibility that OLP diagnoses might not always be correct cannot be overruled given the nonspecificity of OLP histopathology. Another epidemiological observation that cannot be neglected suggests a strict connection between LP and HCV infection. Specifically, this perspective has to do with a disease that is certainly HCV related: porphyria Cutanea Tarda (PCT). All arguments that have been made for the LP-HCV connection have been made for PCT as well. Yet, the explanation that is universally accepted is the geographical one: PCT is prevalent in the regions in which HCV infection is prevalent, and nobody contests that HCV is the major etiologic factor of PCT. Even the combination of the three diseases has been reported (3). Certainly, HCV is not the sole cause of LP. In my view, LP is a cell-mediated immune reaction to various agents, including viruses, the most important of which are hepatotropic. In fact, LP is a relatively rare but well-recognized reaction to HBV vaccination (4).
The real problem may simply be that most studies are retrospective, which makes it difficult to establish whether HCV exposure occurs prior to or after the onset of LP. The occurrence of LP reactions after HBV vaccination irrespective of the type of vaccine used, however, strongly suggests that LP occurs after the infection. I agree with the authors that no definite conclusion can be reached at this point and also with their statement that "screening of LP patients with ELISA is cost-effective only with the presence of other risk factors". The safety of patients and of oral specialists deserves attention in hyperendemic countries, and LP, regardless of the site affected, provides an invaluable clue in this regard.
References:
1. Mahboobi N, Agha-Hosseini F, Lankarani K. Hepatitis C Virus and Lichen Planus: The Real Association. Hepat Mon. 2010;10(3):161-4. [Hepat Mon]
2. Rebora A. Lichen planus and the liver. Lancet. 1981;2(8250):805-6. [PubMed]
3. Mouly F, Pawlotsky JM, Schaeffer A, et al. Association of porphyria cutanea tarda and lichen planus in a patient with chronic hepatitis C virus infection. Br J Dermatol. 1995;132(1):158-9. [PubMed]
4. Drago F, Rebora A. Cutaneous immunologic reactions to hepatitis B virus vaccine. Ann Intern Med. 2002;136(10):780; author reply -1. [PubMed]
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