Showing posts with label Lichen Planus. Show all posts
Showing posts with label Lichen Planus. Show all posts

Tuesday, October 24, 2017

October Series From HCV Advocate - HCV and Peripheral Neuropathy

New Online: HCV-related diseases

In October, HCV Advocate launched a series of patient-friendly articles about the Extrahepatic Manifestations of Hepatitis C, written by Alan Franciscus.

Browse through topics provided below, make sure not to miss new articles published later this month, sign up here to receive updates, follow HCV Advocate on Twitter or connect on Facebook. Find out what's new, here!

Begin with HCV Advocates Extrahepatic Manifestation Glossary and Fact Sheets.

October Blog Special
Extrahepatic Manifestations of Hepatitis C—Peripheral Neuropathy | Alan Franciscus
October 24, 2017
In the past, peripheral neuropathy was believed to be confined to people only infected with hepatitis C-related cryoglobulinemia, but now it is known that peripheral neuropathy may occur even in the absence of cryoglobulinemia.
Continue reading (LINK)

Friday, July 14, 2017

Extrahepatic manifestations of HCV & Treatment

If you are interested in reading full text articles about the treatment and management of HCV I highly suggest you follow Henry E. Chang on Twitter.

Latest Tweets By @HenryEChang on the extrahepatic manifestations of HCV.

July 14, 2017
Extrahepatic manifestations of HCV: The role of direct acting antivirals
María Laura Polo and *Natalia Laufer
Expert Review of Anti-infective Therapy DOI: 10.1080/14787210.2017.1354697

Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations.

This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions.  Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.
Link - Download Full Text Article.......

Clinics in Liver Disease, Volume 21, Issue 3

Chronic Hepatitis C Virus Infection and Depression
Luigi Elio Adinolfi, Riccardo Nevola, Luca Rinaldi, Ciro Romano, Mauro Giordano

HCV Depression Quality of life


Depression is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection reported in one-third of patients.

The prevalence of depression in patients with HCV has been estimated to be 1.5 to 4.0 times higher than that observed in the general population.

Direct HCV neuro-invasion, induction of local and systemic inflammation, neurotransmission, and metabolic derangements are the hypothesized pathogenic mechanisms of depression.

Depression considerably impacts health-related quality of life of HCV-positive patients.

Clearance of HCV by antiviral treatments is associated with an improvement of both depression and quality of life.
Link - Download Full Text PDF

Metabolic Manifestations of Hepatitis C Virus
Lawrence Serfaty

Hepatitis C Steatosis Hypobetalipoproteinemia Microsomal triglyceride transfer protein Insulin resistance. Tumor necrosis factor


Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia.

A strong link between HCV infection and diabetes mellitus has been found in subjectbased studies and, to a lesser degree, in population-based studies.

HCV-mediated insulin resistance may be promoted through multiple pathogenic mechanisms, such as direct inhibition of insulin signaling pathway by HCV core protein in the liver, overproduction of tumor necrosis factor-alpha, oxidative stress, modulation of incretins, or pancreatic ß-cells dysfunction.
Link - Download Full Text PDF

Neurologic manifestations of hepatitis C virus infection
Sentia Iriana, MD, Michael P. Curry, MD, Nezam H. Afdhal, MD, DSc

Hepatitis C Fatigue Neurocognition MR spectroscopy Interferon Ledipasvir/sofosbuvir Cerebrovascular disease

The extrahepatic manifestations of hepatitis C virus (HCV) in the brain include neurocognitive dysfunction, which is manifested by subtle changes in memory, attention, and processing speed.

Neurocognitive defects are independent of the histologic stage of disease and may be induced by a direct effect of HCV on microglial cells or mediated by systemic cytokines crossing the blood-brain barrier.

Magnetic resonance spectroscopy demonstrates abnormal metabolism in basal ganglia and prefrontal and frontal cortex, which has been associated with fatigue and abnormal neurocognitive testing. Interferon and direct-acting antiviral therapy can improve cerebral metabolism and neurocognition if a sustained virologic response is obtained.

Cerebrovascular events and mortality are increased in patients with HCV and may be through an increased risk of carotid artery disease and plaque formation.
Link - Full Text PDF Article

Rheumatologic manifestations of hepatitis C virus
Patrice Cacoub, Cloé Comarmond, Anne Claire Desbois, David Saadoun

Hepatitis C (HCV) Rheumatic disorders Arthritis Vasculitis Arthralgia Sicca syndrome

Main rheumatologic manifestations reported with hepatitis C virus (HCV) chronic infection include arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.

Immunologic factors predisposing to developsuch manifestations include stimulation of B cells, expansion of B-cell–producing immunoglobulin M with rheumatoid factor activity and of clonal marginal zone, like B cells, and a decrease of regulatory T cells.

The treatment of HCV infection with interferon alpha has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders.

New oral interferon-free combinations now offer an opportunity for patients with HCV extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a high efficacy rate and a low risk of side effects.
Link - Full Text PDF Download

Other EHM of HCV infection (pulmonary, idiopathic thrombocytopenic purpura, nondiabetes endocrine disorders
Daniel Segna, Jean-François DuFour

Hepatitis C Extrahepatic manifestations Pulmonary Endocrine Idiopathic thrombocytopenic purpura


Hepatitis C Virus (HCV) infection may increase the risk for obstructive, interstitial, and vascular lung disease, lung cancer, and mortality in HCV-infected lung transplant recipients.

HCV infection may increase the risk of idiopathic thrombocytopenic purpura, nonresponse to corticosteroids during the treatment, and higher rates of splenectomy.

HCV infection may increase the risk of autoimmune thyroiditis, infertility, growth hormone and adrenal deficiency, osteoporosis, and low-trauma fractures.

Targeted prospective cohorts may confirm these results mostly obtained from small casecontrol studies with different study populations and low level of evidence.
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Hepatitis C Virus–Associated Non-Hodgkin Lymphomas
Gabriele Pozzato, Cesare Mazzaro, Valter Gattei

Hepatitis C virus Marginal zone lymphoma Non-Hodgkin lymphoma Direct antiviral agents

Eradication of hepatitis C virus (HCV) in indolent non-Hodgkin lymphomas (NHLs), especially in marginal zone lymphomas(MZLs), determines the regression of the hematological disorder in a significant fraction of cases.

Because direct antiviral agents (DAAs) show an excellent profile in terms of efficacy, safety, and rapid onset of action, these drugs can be used in any clinical situation and the presence of any comorbidities.

To avoid the progression of the NHL, despite HCV eradication, antiviral therapy should be provided as soon as the viral infection is discovered; before that, the chronic antigenic stimulation determines the irreversible proliferation of neoplastic B cells.
Link - Full Text PDF Download

Dermatologic manifestations of chronic hepatitis C
Mehmet Sayiner, Pegah Golabi, Freba Farhat, Zobair M. Younossi

Hepatitis C Extrahepatic manifestation Dermatologic manifestation Cryoglobulinemia Porphyria Lichen planus

HCV infection is associated with several dermatologic diseases, such as symptomatic mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda, and necrolytic acral erythema.

Most of the dermatologic manifestations may be caused by immune complexes. In the interferon and ribavirin era, treatment was associated with dermatologic side effects.

The new generation of interferon-free and ribavirin-free anti-HCV regimens is devoid of dermatologic side effects.
Link - Full Text PDF Download

Hepatitis C Infection - A systematic disease
Zobair M. Younossi
Hepatitis C virus Hepatic complications Extrahepatic complications

It is critical to recognize that hepatitis C virus (HCV) infection is a multifaceted systemic disease with both hepatic and extrahepatic complications.

The comprehensive burden of HCV should not only include its clinical burden, but also its burden on the economic and patient-reported outcomes.

It is only through this comprehensive approach to HCV infection that we can fully appreciate its true burden, and understand the full benefit of curing HCV for the patient and the society.
Link - Download PDF

Thank you Henry E. Chang

Friday, November 2, 2012

Candidiasis and other oral mucosal lesions during and after interferon therapy for HCV-related chronic liver diseases

Research article

Candidiasis and other oral mucosal lesions during and after interferon therapy for HCV-related chronic liver diseases

Yumiko Nagao, Kouji Hashimoto and Michio Sata

BMC Gastroenterology 2012, 12:155 doi:10.1186/1471-230X-12-155
Published: 2 November 2012

Download complete article available as a provisional PDF

Abstract (provisional)

Oral lichen planus (OLP) is seen frequently in patients with hepatitis C virus (HCV) infection. The aim of this study was to evaluate the occurrence of oral candidiasis, other mucosal lesions, and xerostomia during interferon (IFN) therapy for HCV infection.


Of 124 patients with HCV-infected liver diseases treated with IFN therapy in our hospital, 14 (mean age 56.00 +/- 12.94 years) who attended to receive administration of IFN once a week were identified and examined for Candida infection and other oral lesions and for the measurement of salivary flow. Serological assays also were carried out.


Cultures of Candida from the tongue surfaces were positive in 7 (50.0%) of the 14 patients with HCV infection at least once during IFN therapy. C. albicans was the most common species isolated. The incidence of Candida during treatment with IFN did not increase above that before treatment. Additional oral mucosal lesions were observed in 50.0% (7/14) of patients: OLP in three (21.4%), angular cheilitis in three (21.4%) and recurrent aphthous stomatitis in one (7.1%). OLP occurred in one patient before treatment with IFN, in one during treatment and in one at the end of treatment. 85.7% of the oral lesions were treated with topical steroids.

We compared the characteristics of the 7 patients in whom Candida was detected at least once during IFN therapy (group 1) and the 7 patients in whom Candida was not detected during IFN therapy (group 2). The prevalence of oral mucosal lesions (P=0.0075) and incidence of external use of steroids (P=0.0308) in group 1 were significantly higher than in group 2.

The average body weight of group 1 decreased significantly compared to group 2 (P=0.0088). Salivary flow decreased in all subjects throughout the course of IFN treatment and returned at 6th months after the end of treatment. In group 1, the level of albumin at the beginning of the 6th month of IFN administration was lower than in group 2 (P=0.0550). According to multivariate analysis, one factor, the presence of oral mucosal lesions, was associated with the detection of Candida. The adjusted odds ratio for the factor was 36.00 (95% confidence interval 2.68-1485.94).


We should pay more attention to oral candidiasis as well as other oral mucosal lesions, in patients with weight loss during IFN treatment.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Thursday, April 12, 2012

A retrospective case-control study of hepatitis C virus infection and oral lichen planus in Japan

A retrospective case-control study of hepatitis C virus infection and oral lichen planus in Japan: association study with mutations in the core and NS5A region of hepatitis C virus

Yumiko Nagao and Michio Sata
BMC Gastroenterology 2012, 12:31 doi:10.1186/1471-230X-12-31

Published: 10 April 2012
Abstract (provisional)

The aims of this study were to assess the prevalence of hepatitis C virus (HCV) infection in Japanese patients with oral lichen planus and identify the impact of amino acid (aa) substitutions in the HCV core region and IFN-sensitivity-determining region (ISDR) of nonstructural protein 5A (NS5A) associated with lichen planus.

In this retrospective study, 59 patients (group 1-A) with oral lichen planus among 226 consecutive patients who visited our hospital and 85 individuals (group 1-B, controls) with normal oral mucosa were investigated for the presence of liver disease and HCV infection. Risk factors for the presence of oral lichen planus were assessed by logistic regression analysis. We compared aa substitutions in the HCV core region (70 and/or 91) and ISDR of NS5A of 12 patients with oral lichen planus (group 2-A) and 7 patients who did not have oral lichen planus (group 2-B) among patients (high viral loads, genotype 1b) who received interferon (IFN) therapy in group1-A.

The prevalence of anti-HCV and HCV RNA was 67.80% (40/59) and 59.32% (35/59), respectively, in group 1-A and 31.76% (27/85) and 16.47% (14/85), respectively, in group 1-B. The prevalence of anti-HCV (P < 0.0001) and HCV RNA (P < 0.0001) in group 1-A was significantly higher than those in group 1-B. According to multivariate analysis, three factors - positivity for HCV RNA, low albumin level (<4.0 g/dL), and history of smoking - were associated with the development of oral lichen planus. The adjusted odds ratios for these three factors were 6.58, 3.53 and 2.58, respectively, and each was statistically significant. No significant differences in viral factors, such as aa substitutions in the core region and ISDR of NS5A, were detected between the two groups (groups 2-A and -B).

We observed a high prevalence of HCV infection in patients with oral lichen planus. Longstanding HCV infection, hypoalbuminemia, and smoking were significant risk factors for the presence of oral lichen planus in patients. It is advisable for Japanese patients with lichen planus to be tested for HCV infection during medical examination.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Monday, September 5, 2011

Association between lichen planus and Hepatitis C

An association between lichen planus and Hepatitis C virus exists Critical Summary Prepared by: Francesco Chiappelli Ph.D

A Critical Summary of:
Hepatitis C virus infection and lichen planus: a systematic review with meta-analysis
Lodi, G., Pellicano, R., Carrozzo, M.. Oral Diseases. 2010;16(7):601-12

Clinical Questions:
In patients with Hep C infection, is there an increased prevalence of LP diagnoses, compared to patients without the HepC seropositive status?, and conversely is LP prevalence increased in HepC seropositive patients, compared to those without HepC infection?

Review Methods:
The authors examined five search engines. Only observational studies of patients with HepC seropositivity in which there was a comparison/control group were included. Studies were excluded if there was a potential that the LP patients were co-infected with HepC. All languages were included. Two independent screeners determined eligibility of the reports. A third reviewer resolved any disagreements. The authors assessed risk of bias (Yes, No, Unclear) according to random patient sampling, matching of the control group, and design (prospective vs. retrospective). Low bias risk studies satisfied all the criteria; high bias risk studies failed to satisfy one or more criterion. Selected studies included subjects and control groups positive for HepC among patients with LP, or those positive for LP among HepC seropositive patients. The authors calculated odds ratio (OR), with 95% confidence intervals (CI95). The authors tested heterogeneity and publication bias, and interpreted meta-analysis results with the fixed effect model.

Main Results:
Lichen planus (LP) leads to an increased risk (OR: 4.85, CI95: 3.58-6.56) of being HepC seropositive, and HepC seropositive patients are at increased risk of LP (OR: 4.47, CI95: 1.84-10.86). Risk ratios vary in different geographical regions: the risk of LP is higher among HepC seropositive patients than controls in Southern Europe (OR: 4.26, CI95: 1.13–16.10) and the United States (OR: 5.09; CI95: 1.33–19.41). Risk ratio of HepC seropositivity among patients with LP younger than 50 is significantly greater than in age-matched controls (OR: 3.43, CI95: 2.02–5.85)
HepC seropositivity increases the risk for LP, particularly among subjects younger than 50 years of age, and the risk of LP varies in different regions of the world, being higher among HepC seropositive patients than controls in the Mediterranean basin and in the United States.
Source of funding:

Importance and Context:
Lichen planus is a relatively common disorder of the stratified squamous epithelia. It frequently involves the oral cavity (OLP). A chronic condition that primarily affects peri/post-menopausal women, OLP may be pre-malignant. There is no cure for OLP; only palliative treatment for the more severe OLP lesions. With regard to hepatitis, most HepC seropositive patients are not aware of their HepC infection. Chronic HepC infection can lead to cirrhosis and hepatocellular carcinoma. Increased health literacy about HepC and LP will contribute to improve the patients’quality of life.

Strengths and Weaknesses of the Systematic Review:
The study has sound research synthesis protocol for obtaining the sample of studies and doing the preliminary screening. The authors present adequate transformation of the data to odds ratio and CI, and stringent meta-analysis and related tests of homogeneity and publication bias. The ratings of risk bias, which the authors term “quality”, and the ratings of the dimension the authors refer to as global validity are weak ad-hoc measures, with no validation data. The ORs were not significantly different when studies were excluded from the meta-analysis, based on the authors’ global validity scale.

Strengths and Weaknesses of the Evidence:
The evidence of association between HepC and LP is significant. Even when studies with high and moderate risk of bias are excluded from the meta-analysis, the outcomes show statistical significance. The clinical question does not lend itself to randomized clinical trials; therefore, the types of studies selected, while not having the optimally higher level of evidence, are the strongest we have to determine association, but cannot but yield the overall limited evidence of this systematic review. The assessment of the quality of the evidence (i.e., risk bias) was not validated satisfactorily; and this contributes to the overall limited evidence.

Implications for Dental Practice:
There is a strong link between the presence of OLP and HepC seropositivity, but most patients with HepC are asymptomatic. Dentists may be able to alert OLP patients to a potential for HepC infection. Early diagnosis and a proper management of HepC seropositivity and OLP might save lives and reduce health care costs.
Critical Summary Publication Date: 9/5/2011

Systematic Review Conclusion:
Hepatitis C (HepC) infection places people at increased risk of developing lichen planus (LP), including in the oral cavity (oral lichen planus, OLP), but the association varies in different regions of the world, with people from the United States among the groups at highest risk.
Critical Summary Assessment:
Limited evidence suggests an association between HepC seroprevalence in patients with LP as well as the prevalence of LP in patients with HepC infection.
Evidence Quality Rating:

These summaries are not intended to, and do not, express, imply, or summarize standards of care, but rather provide a concise reference for dentists to aid in understanding and applying evidence from the referenced systematic review in making clinically sound decisions as guided by their clinical judgment and by patient needs. American Dental Association ©

Friday, March 4, 2011

Hepatitis C Lichen Planus:Editorial W-Follow Up Correspondence

Related On The Blog;Rash Hepatitis C /Lichen planus /Photos "A study on the association with hepatitis B and hepatitis C in 1557 patients with lichen planus"
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
2 Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
3 Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


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.

Association between hepatitis C virus and oral lichen planus

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


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.


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.


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

Rebora AC7O Clinica Dermatologica dell’Università, University of Genoa, Genoa, Italy
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:
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.


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.

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.
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.
4. Drago F, Rebora A. Cutaneous immunologic reactions to hepatitis B virus vaccine. Ann Intern Med. 2002;136(10):780; author reply -1.

Related On The Blog;Rash Hepatitis C /Lichen planus /Photos


Wednesday, December 15, 2010

Hepatitis C Virus Infection: A Simple and Updated Approach for Extrahepatic Manifestations

Also See:
Hepatitis C Virus as a Multifaceted Disease: A Simple and Updated Approach for Extrahepatic Manifestations of Hepatitis C Virus Infection
Khattab MA
Department of Internal Medicine, Minia University, Minia, Egypt
Eslam M
Department of Internal Medicine, Minia University, Minia, Egypt

Alavian SM
2 Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran

Mahmoud Aboelneen Khattab,
Department: Department of Internal Medicine, Minia University
Address: Department of Internal Medicine, Minia University, Minia, Egypt, p.o.Box: 61111
City: Minia
Country: Egypt
Tel: +20-225191818, +20-862378181
Fax: +2086242813


Hepatitis C virus infection is an emerging disease and a public health problem in the world. There are accumulating data regarding extra hepatic manifestation of HCV, such as rheumatologic manifestations, endocrine, hematologic, dermatologic, renal, neurologic, and systemic manifestations. The therapy of them needs more attention to some exacerbations of extra hepatic manifestation and in some situation it needs different approaches. In this review we tried to provide latest evidence for extra hepatic manifestation and management of them.



Hepatitis C virus (HCV) is a major cause of liver-related morbidity and mortality worldwide and represents a major public health problem (1-6). HCV can spread parenterally through contact with infected blood, transfusion of infected blood and its products, intravenous drug use, contamination during medical procedures, and a lack of attention to health precautions. Despite a declining incidence of new infections (7, 8), the burden of the disease, both in terms of mortality and cost, is expected to increase over the next decade, and HCV infection will maintain to be a potential cause of morbidity and mortality and need for transplantation in the future (9, 10). It is estimated that around 170 to 200 million individuals are living with HCV infection worldwide (11, 12), and there is significant geographical variation in the prevalence of HCV infection across countries and regions (1, 13). Although HCV is a hepatotropic virus, in some patients the primary manifestations of infection occur outside the liver. There is a growing body of evidence to support the idea that HCV can replicate efficiently in extrahepatic tissues including the PBMC. Autoimmune manifestations are common in patients chronically infected by HCV (14). These manifestations can be dominant, whereas the hepatic disease can be quiescent or mild. More recently, there has been growing interest in the relationship between HCV and Sjogren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE(15). Depending on the pathogenic and epidemiological evidence provided by different studies; the extrahepatic manifestations of HCV infection (EHMs-HCV) can be classified into four categories:
1. EHMs-HCV characterized by a very strong association demonstrated by both epidemiological and pathogenetic evidence (e.g., mixed cryoglobulinemia);
2. EHMs-HCV include disorders for which the significant association with HCV infection is supported by enough data to clearly show a higher prevalence of HCV than in controls but still have unclear pathogenic mechanisms (e.g., B-cell-derived non-Hodgkin's lymphoma [NHL], diabetes mellitus, porphyria cutanea tarda, lichen planus);
3. EHMs-HCV includes the associations for which the high prevalence in HCV populations could be due to HCV infection or confounding factors, and thus these associations still require confirmation and a more detailed characterization with respect to similar pathologies of different etiology or idiopathic nature (e.g., idiopathic pulmonary fibrosis, autoimmune thyroiditis, sicca syndrome, noncryoglobulinaemic nephropathies and glomerulonephritis, and aortic atherosclerosis);
4. EHMs-HCV includes only anecdotal observations (e.g., growth hormone defficiency, chronic pruritus, cardiomyopathy, psoriasis, peripheral or central neuropathies, chronic polyarthritis, rheumatoid arthritis, polyarthritis nodosa, behcet's syndrome, poly or dermatomyositis, necrolytic acral erythema, and autoimmune hemolytic anemia).

1. Mixed Cryoglobulinemia
Mixed Cryoglobulinemia (MC) is the most documented and closely associated disorder with HCV (16, 17). The prevalence of HCV-infected patients with coexisting circulating MC ranges from less than 10% to greater than 50%; however, overt vasculitis manifestations are seen in only 2% to 3% of these patients (18-20). This variability may represent geographic and population-specific factors involved in the development of MC, differences in the definition of the disease, and laboratory techniques for diagnosis. The disease occurs as a result of chronic immune-system stimulation leading to B-cell clonal expansion and immune-complex (IgG, IgM, RF complement, HCV-LDL/VLDL) production. These immune complexes will often take the form of cryoglobulins (21-23). Cryoglobulins are monoclonal or polyclonal immunoglobulins that reversibly precipitate at low temperatures; cryoglobulinemia occurs when these proteins are present in the circulation (24). Clinical manifestations of MC are secondary to a systemic immune-complex-related vasculitis involving small vessels.

Diagnosis of Cryoglobulinemia
Nowadays, there are no standardized criteria for the diagnosis of MCS. However, valuable classifications have been proposed by the Italian Group for the Study of Cryoglobulinemia (24). Diagnosis is based on clinicopathological and laboratory findings. Cryoglobulinemia may be suspected if the patient has positive rheumatoid factors. Clinically, asymptomatic serum MC can be found in some individuals chronically infected with HCV (24, 25); a condition that may precede the clinical onset of the disease by years or decades. Glomerulonephritis, peripheral neuropathy, and generalized vasculitis are the common complications of cryoglobulinemia (26-28).
Palpable purpura (Figure. 1) is the most common clinical finding, occurring in 90% of cases. The association between MC and severe liver damage or steatosis has been discussed widely (29-31). Several studies have shown an epidemiological association between MC and severe liver damage (29). However, the pathogenetic mechanisms of such an association have not been clearly identified. The laboratory work-up of cryoglobulinemia vasculitis includes cryoglobulin testing, quantification of total serum protein and immunoglobulins, complement levels, evaluation of serum for monoclonal gammopathy, RF activity, virological markers (anti-HCV antibodies, HCV RNA, hepatitis B virus serology, hepatitis B virus DNA, and others), blood chemistry, and urine analysis. Leukocytoclastic vasculitis, involving medium- and, more often, small-sized blood vessels (arterioles, capillaries, and venules) is the typical pathological finding of involved tissues. Leukocytoclastic vasculitis is easily detectable by means of skin biopsy of recent vasculitis lesions (within the first 24 to 48 hours (24, 32, 33).


Figure 1. Nonblanching erythematosus papules are the notable findings of these palpable purpura, which are characteristic of the vasculitis associated with MC.

Treatment options
Treatment can eradicate HCV infection (etiologic therapy), suppress B-cell clonal expansion and cryoglobulin production (pathogenetic therapy), or ameliorate symptoms (symptomatic therapy).

Etiologic therapy
Under ideal circumstances, the treatment of MC aims to eradicate the HCV infection. Treatment of MC with interferon (IFN) therapy is associated with a relatively poor response (34, 35); however, PEG-IFN plus RBV show better results (36, 37). The goal of therapy in those patients is not limited to a sustained virologic response; rather, patients might see an improvement in their renal manifestations with prolonged treatment courses. However, clinical improvements are often transient and restricted to patients with mild to moderate disease activity (36-38). Moreover, IFN therapy can induce an exacerbation of various vasculitis manifestations (i.e., glomerulonephritis, neuropathy), and RBV, due to its renal elimination, may be contraindicated in patients with severe renal impairment.

Pathogenetic therapy
This therapy is currently used when antiviral therapy is not recommended. Treatment should be limited to the time (weeks or months) required for symptom remission. Several alternative therapies may be adopted, which include corticosteroids due to its anti-inflammatory and immunosuppressive actions (at high doses: 1 mg/kg daily or 0.5-1 g). However, the disadvantage of favoring the etiologic agent is that it can lead to increased viral replication (39). Immunosuppressive drugs (e.g., Cyclophosphamide, Chlorambucil, and Azathioprine) are used to suppress antibody and cryoglobulin production (40, 41). The most effective and commonly used cytotoxic drug is Cyclophosphamide, given orally at doses of 2 mg/kg per day. Recently; Mycophenolate Mofetil (1 g twice a day) can be used as a less toxic alternative to Cyclophosphamide for the induction of remission in MC vasculitis; Mycophenolic Acid is more selective than Cyclophosphamide in inhibiting lymphocyte proliferation and functions. Interestingly, Mycophenolic Acid seems to reduce viremia in HCV-infected renal or heart-transplant recipients due to its ability to inhibit inosine monophosphate dehydrogenase, the same target enzyme inhibited by RBV (42). However, data supporting this approach are limited and almost exclusively derived from anecdotal reports (43). For patients unresponsive to treatment with steroids or other immunosuppressants, the administration of the novel immunosuppressant Rituximab; a chimeric monoclonal antibody directed against CD20 antigen on B cells, has been recently proposed for the pathogenetic treatment of HCV-related MC (44, 45). By depleting B cells, Rituximab has the potential to reduce the development of plasma cells, thereby limiting Cryoglobulin production. Rituximab, at the standard dose of 375 mg/m2 weekly for 4 weeks proved to be a safe and effective treatment for most patients with HCV-MC, leading to significant clinical improvement as a consequence of both B-cell depletion and decreases in serum Cryoglobulin levels (44-48). Although fever, chills, nausea, vomiting, urticaria, orthostatic hypotension, and bronchospasm occur in more than 80% of patients, these side effects are generally mild and limited to the infusion period. An increase in viral load, without significant variations in liver-function tests, has been detected after rituximab treatment (44) To reduce HCV replication, a combination of Rituximab with antiviral agents has been suggested.
Because the median duration of the response to Rituximab therapy is about 1 year, a relapse of cryoglobulinemic vasculitis may develop following treatment. Relapses are preceded by peripheral B-cell repletion. It is unknown whether maintenance therapy with Rituximab is better than retreatment after relapse. Plasmapheresis can be used as an effective adjuvant therapy to treat severe exacerbations of cryoglobulinemic vasculitis, particularly active cryoglobulinemic glomerulonephritis. Both traditional plasma exchange and double-filtration plasma exchange are able to markedly reduce the levels of circulating immune complex, especially the cryoglobulins. Oral Cyclophosphamide (50 to 100 mg/day for 2 to 6 weeks) during the tapering of apheretic sessions can reinforce the beneficial effect of plasma exchange; moreover, it can prevent the rebound phenomenon that may be observed after the discontinuation of aphaeresis (33).

Symptomatic Therapy
The hypoantigenic diet (LAC) diet consists of a diet with reduced content of alimentary macromolecules with high antigenic properties, allowing for more efficient removal of CGs by the reticuloendothelial system. This diet can improve minor manifestations of the disease (purpura, arthralgias, paresthesias) and is generally prescribed at the initial stage of the disease (49). Colchicine, an anti-inflammatory agent with a relatively selective effect for gouty arthritis, has been proposed for MC patients with mild to moderate levels of the disease. In an uncontrolled trial, colchicine (1 mg/day for 6 to 48 months) improved clinical and laboratory variables (particularly cryocrit; (50). However, its toxicity and the availability of alternative, less toxic agents have substantially lessened its use.

2. Lymphoproliferative disorders (LPD)
HCV-associated LPD can be observed during the course of MC or in non-MC-related idiopathic forms (51). A recent, large-scale, retrospective cohort study suggests that HCV infection confers a 20-30% increased risk of NHL overall (52). These results were confirmed in a meta-analysis by Dal Maso and Franceschi, which included 15 case-controlled studies and 3 cohort studies and demonstrated a pooled risk ratio (relative risk [RR]) of 2.0 (95% CI, 1.8 to .2) for the cohort studies and 2.5 (95% CI, 2.1 to 3.1) for the case-controlled studies for the development of B-cell NHL in HCV-infected patients (53). The meta-analysis did not show differing RRs for NHL subtypes. From a histopathological point of view, although virtually all types of lymphoid malignancy can be found in patients with HCV infection, the strongest association is with NHL, and the vast majority of NHL is low grade with predominantly extranodal involvement. According to the REAL/WHO classifications, the most prevalent HCV-associated LPDs are follicular lymphoma, B-cell chronic lymphocytic leukemia or small lymphocyte lymphoma, diffuse large B-cell lymphoma, and marginal zone lymphoma, including the mucosa-associated lymphoid tissue lymphoma (54). Overall, marginal-zone lymphoma appears to be the most frequently encountered low-grade B-cell lymphoma in HCV patients (55). Regarding the pathogenesis of the HCV-associated LPDs, the majority of studies pinpoint two presumable mechanisms. The first is indirect; specifically, by relying on the chronic nature of HCV infection, chronic antigenic stimulation may lead to an overexpression of B-cells favoring certain clones. This mechanism could explain the immune dysregulation leading to autoimmunity, MC, and eventually malignant transformation (56). The second mechanism is direct, relying on the particular lymphotropism of HCV and therefore on the high invasion of B-cells by HCV (57). Both mechanisms lead simultaneously through complex, multistep, pathogenic pathways. There may be genetic and environmental factors that further explain the final steps to malignant transformation. Rearrangement of the antiapoptotic bcl-2 gene with t(14;18) translocation is the most common chromosomal translocation in lymphoid cancers, especially follicular lymphoma, a subtype of NHL. Thirty-five percent of patients with chronic HCV infection have evidence of the t(14;18) translocation in their peripheral mononuclear cells, which may further contribute to lymphomagenesis (58). Mutations in other oncogenes, such as c-myc, and regulators of apoptosis may be the important missing link to our understanding of lymphomagenesis in the setting of chronic HCV infection.

Hepatitis C Virus and Monoclonal Gammopathy
Serum monoclonal gammopathy (MG) is an extrahepatic manifestation of HCV infection. A prospective study by Andreone et al. found 11% of monoclonal bands in HCV-positive patients versus 1% in HCV-negative patients, demonstrating a significant prevalence of monoclonal gammopathy in HCV-related liver disease (59). Actually, a few HCV positive patients with MG can be considered affected by myeloma according to clinico-pathological characteristics; the US Veterans Affairs database evaluated by Giordano et al. revealed an increased risk for the development of Waldenström's macroglobulinemia (hazard ratio=2.76) with no associated increased risk of development of multiple myeloma in HCV patients (52).

Therapy for HCV-related LPD
Recent studies support the rationale for the use of antiviral therapy in the context of low-grade HCV-positive NHL regardless of histological subtype (60-62).
Interestingly, in these studies, there is a clear correlation between HCV viral-load reduction and clinical response in LPD-infected patients. In intermediate and high-grade NHL, chemotherapy is usually necessary and antiviral treatment may serve as maintenance therapy after the completion of chemotherapy (63). Because chemotherapy may lead to a substantial increase in the levels of viremia, cautious monitoring of the HCV RNA levels and transaminases is important; still, a consecutive exacerbation of the infection, making discontinuation of chemotherapy mandatory, is not unlikely to occure (63). Regular monitoring of transaminases during treatment is essential because HCV-positive patients seem to experience increased short-term hepatic toxicity from chemotherapy. The use of rituximab either in monotherapy or in combination with antiviral treatment or chemotherapy or both appears promising (64, 65), however more studies are needed to define the actual role of rituximab in treatment and recovery.

3. HCV-associated arthritis (HCV-AR)
Rheumatologic complications of HCV infection are common and include MC, vasculitis, Sjogren's syndrome, arthritis, and fibromyalgia (66, 67). There is a well-defined picture of arthritis associated with the presence of MC that consists of an intermittent mono- or oligoarticular, nondestructive arthritis affecting large- and medium-size joints (66, 68). Joint involvement is the most frequent extrahepatic manifestation of HCV infection. The HCV-associated rheumatic manifestation varies from 2% to 23%, depending on the geographic region and the design of the studies (69-73). HCV-AR commonly presents as a rheumatoid-like, symmetrical polyarthritis (SP) involving mainly small joints or less commonly as intermittent mono- or oligoarthritis in large joints (IMO(74, 75). The different diagnosis between SP and other polyarthritides, especially rheumatoid arthritis (RA), can be a clinical challenge (68, 72). HCV-AR is similar to RA, but it usually runs a relatively benign course that, in contrast to true RA, is typically nondeforming and is not associated with articular bony erosions. Furthermore, unlike classic RA, ESR is elevated only in about half of the patients, and subcutaneous nodules are absent (76). In the diagnosis; SP frequently meets American College of Rheumatology's classification criteria for RA. However, anticyclic citrullinated peptide antibodies (anti-CCP) provide an important clue in distinguishing RA from HCV-AR because anti-CCP is considered to be specific for RA (77, 78). Positive HCV antibody and HCV RNA, as well as the absence of bony erosions and subcutaneous nodules may be useful in distinguishing between HCV-related arthritis and RA. Risk factors for HCV infection such as transfusion and IV drug abuse or a history of hepatitis should be included in the history of present illness of any patient with polyarthritis (79). In such patients serologic studies for hepatitis C should be performed (79). Table 1 may provide help in these differentiations.

Table 1. Comparison between HCV-associated arthritis and rheumatoid arthritis


*In patients with HCV-associated arthritis and MC: RF positivity (virtually 100%). Low C4 levels (50-85%)

The optimal treatment for HCV-related arthritis has not yet been established and very little evidence about the treatment of HCV-AR has been reported in the literature (76). Patients with HCV-AR in the absence of cryoglobulinemia have been treated successfully with NSAIDs, hydroxychloroquine, and low doses of prednisone (80). The IMO subset is usually responsive to low doses of corticosteroids with or without hydroxychloroquine (33). Administration of antiviral treatment (IFN) has not been associated with significant improvement, and in certain cases has exacerbated articular symptoms (80, 81). In a small number of resistant cases, methotrexate was successfully used without significant adverse effects on liver function. Nevertheless, extreme caution with very close monitoring of liver function and viremia levels is needed for patients starting such therapy (81). Another study examined penicillamine as a potential treatment; however, despite an improvement of symptoms, penicillamine did not lead to a complete remission of the disease, and there is no information yet in the literature about the safety of this therapy (82).
In addition, new data has emerged about the role of Cyclosporine in suppressing HCV replication by targeting the cyclophilin B protein, which interacts with the C-terminal region of NS5B and appears to stimulate the RNA binding activity involved in HCV RNA replication (83). These favorable results are predominant for HCV genotype 1b and 4a (84, 85). Because CsA is currently administered to treat several autoimmune disorders including inflammatory joint diseases (86, 87), it may have a potential role in HCV-AR therapy as well. Anti-TNF therapy for RA in the setting of HCV appears to be safe and well tolerated, without apparent influence on the underlying HCV infection; however, the usually nonaggressive course of HCV-related arthritis does not justify the therapeutic use of anti-TNF (88). Recently, a trial evaluated the safety and efficacy of Etanercept in a small group of HCV-AR. Although Etanercept has been reported to be safe, its efficacy does not seem promising, especially given that it produced lower results than those obtained in patients with RA (89). The treatment of RA in patients with coexisting HCV infection is also problematic. First-line disease-modifying drugs such as Methotrexate and Leflunomide are potentially hepatotoxic and should be used with extreme caution (90, 91). In mild cases, Hydroxychloroquine can be tried first with and without low doses of Prednisone (<7.5>


Figure 2. Mechanisms of HCV-induced renal injury


Table 2. Glomerular disease associated with HCV

For all patients, the decision to initiate treatment should be made after weighing the possible benefits and harms of therapy. The recommended therapeutic strategy depends on the severity of the kidney disease. For all patients, the same renoprotective measures (blood-pressure-lowering drugs and antiprotinuric agents) commonly used in patients with chronic nephropathies should be used in patients with HCV-associated GN. Diuretics, lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are potentially beneficial in patients with HCV-associated GN (99). In a recent meta-analysis of clinical, controlled trials of the two treatments (antiviral versus immunosuppressive) described for HCV-related GN, the majority of patients had cryoglobulinemic GN (96). The primary endpoint was the frequency of patients with a reduction of proteinuria (return of proteinuria to normal or a decrease of at least 50%) by the end of therapy. Pooling the results from this study demonstrated that proteinuria decreased more commonly after standard IFN-doses than with corticosteroid therapy and the OR was 3.86 (95% CI, 1.44; 10.33; P=0.007); however, both treatments failed to improve renal function. The authors concluded that the antiviral therapies were more effective than immunosuppressive therapy in lowering proteinuria levels in patients with HCV-related GN, at least in the short term. Therefore, the first-line treatment for patients with mild to moderate clinical and histological kidney damage is antiviral therapy. In case of severe renal involvement (nephrotic syndrome, nephritic syndrome, progressive renal failure, or a high activity score of glomerulonephritis on light microscopy), the initial treatment may consist of sequential administration of immunosuppressive therapies (plasmapheresis, corticosteroids, and cyclophosphamide). Caution should be taken using immunosuppressive therapy in patients with HCV-associated GN because of a concern regarding viral replication (100). For patients unresponsive to steroid and immunosuppressive therapy, preliminary data support the use of rituximab for the treatment of HCV-associated GN (101). This is a human-mouse chimeric monoclonal antibody that selectively depletes B-cell by binding to CD20 cell surface antigen (102). It has been suggested that rituximab has a marked antiproteinuric effect through interference with monoclonal IgM production, cryoglobulin synthesis, and renal deposition of immune complexes (ICs). Recent data notes that Rituximab combined with Peg-IFNα/ribavirin is well-tolerated and more effective than Peg-IFNα/ribavirin in HCV-MC. In a recent prospective cohort study of 38 HCV-MC patients who received a combination of Rituximab (375mg/m² once a week for 1 month) followed by weekly Peg-IFNα (2a, 180mcg or 2b, 1.5mcg/kg) plus ribavirin (600-1,200 mg) daily for 48 weeks were compared to 55 HCV-MC patients who received the same Peg-IFNα and ribavirin treatments. Compared with Peg-IFNα and ribavirin, patients who received rituximab plus Peg-IFNα and ribavirin had a shorter time to clinical remission, better renal-response rates, and a high tolerance for treatment with no worsening of HCV RNA under rituximab (103). Another very recent, long-term trial confirmed these results, which may last for over 3 years (104).

5. HCV and Thrombocytopenia
Several studies have shown that thrombocytopenia is frequently observed in patients with chronic hepatitis C infection (69, 105-108), and a variety of pathogenic mechanisms that are implicated in this abnormal finding are portal hypertension and hypersplenism in the cirrhosis stage, autoimmune reaction to platelets, and direct infection of platelet and megakaryocytes by HCV infection. This may be a sign of extrahepatic manifestation of chronic hepatitis C (109). In cirrhotic patients, sequestration of platelets in the enlarged spleen secondary to portal hypertension can cause thrombocytopenia (105). However, thrombocytopenia also occurs in patients with chronic hepatitis C without cirrhosis. Another mechanism is autoimmune reaction to platelets (110, 111). Some reports indicated that HCV infection may reflect the expression of platelets-associated immunoglobulin G(PAIgG), which can lead to platelets destruction by the reticulo-endothelial system (112, 113). In addition, several studies have suggested that HCV may have a direct pathogenic role in the process leading to thrombocytopenia (105, 114). The incidence of mild thrombocytopenia (defined as a platelet count under 150,000/μl) is between 41% and 50% in patients with HCV infection, whereas severe thrombocytopenia (defined as a platelet count under 50,000/μl) is less common (105, 115).

6. Cutaneous Manifestations of HCV
In addition to MC-related purpura, HCV infection also has been associated with several cutaneous disorders as noted below.

Pruritus is a presenting symptom in 20% of patients (116). Although, the pathogenesis is uncertain, both peripheral (increased plasma level of bile salts) and central mechanisms (increased plasma level of opioids) have been proposed (116). The combination of both bile-salt-lowering and opioid-antagonist strategies appears reasonable in the management of pruritus of cholestasis; treatment options include topical antipruritics, systemic antihistamines, rifampin, naloxone or naltrexone, and ultraviolet B phototherapy (116).

Porphyria Cutanea Tarda (PCT)
PCT is a photosensitivity disorder caused by a decrease in functional uropophryinogen decarboxylase (UROD) and an increase in circulating porphyrins. The prevalence of HCV infection in patients with porphyria is high, ranging from 40% to 50% (Figure 3) (117). HCV does not seem to induce alteration of porphyrin metabolism, although it may induce the disease in genetically predisposed individuals. Meanwhile, some authors suggest that PCT might be related to HCV-induced hepatic iron overload (117). The highest rates of PCT have been observed in patients with HCV-related liver cirrhosis, suggesting that cirrhosis may play a role in its development. Antiviral therapy seems to ameliorate cutaneous lesions, but there is still no randomized clinical trial (117).



Figure 3. Erosions, crust, and blisters are evident on the hands of this patient with PCT.

Lichen Planus (LP)
HCV has been implicated in triggering LP (118). In a recent meta-analysis, LP patients were observed to have significantly higher risk of being HCV seropositive (odds ratio 4.85; 95% CI 3.58-6.56) than controls. A similar odds ratio of having lichen planus was found among HCV patients (4.47; 95% CI 1.84-10.86). Subanalyses indicated that the variability in the association between HCV and lichen planus seemed only partial and dependent on geographic effect Studies. (118). Data from Egypt reveal that the prevalence of LP among CHC patients is around 4% (119). Data suggest that skin and mucosal lesions may be caused by direct action of the virus or immunological response, especially when erosive oral lesions are present, and recently HCV-induced insulin resistance has been implicated in the pathogenesis of LP (118, 120). The skin and the oral cavity are easy to observe, so the presence of LP can be potentially used as a potential marker of HCV in asymptomatic patients (Figure 4) (121).


Figure. 4. The polygonal purple papules of LP are evident on the forearms of a patient with HCV.

LP is associated with a variable response to IFN treatment, and both improvement and exacerbation of symptoms have been reported. The uses of steroids, either topical or injectable, are also used in managing the symptoms (120).

Link between HCV and other clinical disorders
7. Sicca syndrome
Sjögren's syndrome (SS) is an autoimmune disease that involves the exocrine glands and generally induces xerostomia and xeroftalmia (sicca syndrome) due to an involvement of salivary and lachrymal glands in the presence of immunological alterations represented by antinuclear autoantibodies and antiepithelial neutrophil-activating peptide (ANA, SSA/Ro, SSB/La). In the absence of an associated systemic autoimmune disease, patients with similar manifestations can be defined as affected by primary SS. The clinical spectrum of the syndrome ranges from an organ-specific autoimmune disease to a systemic process with different manifestations. SS is recognized in large portions of MC patients (122, 123), and was also observed in CHC patients by Haddad et al. in 1992 (124). In a recent cohort from Egypt, SS's prevalence was reported to be around 9% (73). This syndrome closely resembles primary SS; however, it typically lacks ANA, SSA/Ro, and SSB/La. The pathogenic role of HCV infection in SS remains an issue of debate (125). It has been proposed that HCV infection is a criterion to rule out a primary diagnosis of SS, especially if cryoglobulinemia and hypocomplementemia are present and anti-SSA/Ro antibodies are absent (126, 127).

8. Idiopathic pulmonary fibrosis (IPF)
A pathogenic link between HCV infection and IPF has been suggested by the higher frequency of HCV markers in patients with IPF (128, 129). Whether CHC is linked to pulmonary fibrosis directly or indirectly through underlying cryoglobulinaemia and vasculitis remains issue of discussion (130).

9. Cardiomyopathy and atherosclerosis
A causal relationship with HCV infection has been suspected for several myocardial impairments, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and chronic myocarditis. The pathogeneses of these HCV-associated myocardial impairments probably rely on autoimmune phenomena with the particular involvement of the human major histocompatibility (MHC) class II antigen (131). Moreover, the recent determination of a significantly higher prevalence of carotid or coronary artery atherosclerosis in patients with HCV infection (132, 133) is noteworthy. The recent finding of HCV RNA sequences in plaque tissue strongly suggests an active local infection. This in turn makes it conceivable that the virus may exert local action in carotid atherosclerosis (134).

10. Neuropathy
HCV-neuropathy presents with peripheral neuropathy that involves the legs and is typically very painful, with progression to muscle weakness in some patients. The disorder results from immune-complex deposits within the vasa nervorum of the peripheral nerves leading to vasculitis (135). Antiviral therapy should be applied cautiously in the presence of neuropathy. Although cases of HCV-related peripheral neuropathy responsive to antiviral therapy with IFNα and ribavirin have been described (136), several authors have reported an aggravation of pre-existing MC-related neuropathy or even de novo occurrence of demyelinating polyneuropathy during IFN-α or PEG-IFN-α treatment (137). Therefore, it is presumable that genetic susceptibility and other idiosyncratic factors may influence the response of the HCV-associated neuropathy to IFNα, making close monitoring of the course of this EHM during IFNα treatment indispensable.

11. Thyroid and HCV
Autoimmune thyroid diseases (AITDs) are complex diseases that develop as a result of interactions between genetic, epigenetic, and environmental factors. Significant progress has been made in our understanding of the genetic and environmental triggers contributing to AITD. The high prevalence of AITDs has been reported in HCV-infected patients before and after IFNα therapy (138). Two well-documented environmental triggers of AITD, HCV infection and IFNα therapy, should be given more attention in the field (139). Chronic HCV infection has been shown to be associated with an increased incidence of clinical and subclinical autoimmune thyroiditis (i.e., the presence of thyroid antibodies in euthyroid subjects). The pattern of thyroid disorders observed in HCV infection is characterized by the presence of increased circulating antithyroid peroxidase antibodies (AbTPO) and an increased risk of hypothyroidism in AbTPO-positive subjects (109, 140). The Autoantibodies against internal organs such as the thyroid are common before therapy with IFNα (141). In some cases, antibodies against IFN appear after IFN therapy with in HCV-infected patients (142). Moreover, IFNα therapy for chronic HCV infection is associated with subclinical or clinical thyroiditis in up to 40% of cases, which can be autoimmune or nonautoimmune thyroiditis. In some cases, IFN induced thyroiditis (IIT) in chronic HCV patients may result in severe symptomatology necessitating the discontinuation of therapy. Although the epidemiology and clinical presentation of HCV- and IFN-induced thyroiditis have been well-characterized, the mechanisms causing these conditions are still poorly understood.
Treatment: In cases of symptomatic hyperthyroidism, discontinuation of therapy is recommended. In hypothyroidism, adding thyroid hormone can alleviate the symptoms, making it possible to continue therapy. Thyroid-function tests should be provided every 3 months during the therapy.


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