Hepatitis C virus (HCV) infection: A systemic disease

Available online at www.sciencedirect.com Molecular Aspects of Medicine 29 (2008) 85–95 www.elsevier.com/locate/mam Review Hepatitis C virus (HCV) infection: A systemic disease Antonio Craxı̀ a, Giacomo Laffi b, Anna Linda Zignego b,* a GI & Liver Unit, DI.BI:M.I.S., Policlinico, University of Palermo, Palermo, Italy b Department of Internal Medicine, University of Florence, Florence, Italy Received 27 September 2007; accepted 28 September 2007 Abstract Hepatitis C virus (HCV) infection is a global health problem, being the second most common chronic viral infection in the world with a global prevalence of about 3% (about 180 million people). HCV is both an hepatotropic and a lymphotropic virus; and chronic infection could cause, on one hand, chronic hepatitis, cirrhosis and hepatocellular carcinoma and on the other hand several extrahepatic diseases including, first, mixed cryoglobulinemia and lymphoma. The association between hepatic (hepatocellular carcinoma) and extrahepatic (lymphoma, thyroid cancer) malignancies has justified the inclusion of HCV among human cancer viruses. The pathogenesis of HCV-related sequelae (hepatic or extrahepatic) is not fully understood representing a challenge of prime importance in light of the optimization of clinico-therapeutic management of these patients. Combined treatment with pegylated interferon plus ribavirin is presently the first-line, gold standard treatment of most HCV-related diseases. However, mainly in the case of extrahepatic manifestations, a cautious approach to the patient, with a case to case accurate tailoring of therapy is frequently requested. The present review will outline the principal aspects of such HCV-induced systemic disease focusing on extrahepatic manifestations. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: HCV; Chronic hepatitis; Extrahepatic manifestations; Lymphoproliferative disorders; Mixed cryoglobulinemia; Lymphoma Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Natural course of HCV infection . . . . . . . . . . . . . . . . 1.2. HCV RNA testing . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Extrahepatic conditions linked to HCV infection . . . . . Lymphoproliferative disorders . . . . . . . . . . . . . . . . . . . . . 2.1. Mixed cryoglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 * Corresponding author. Address: Professor of Internal Medicine, MASVE Center, Denothe Center, Department of Internal Medicine, University of Florence, Viale GB Morgagni, 85, 50134 Florence, Italy. E-mail address: a.zignego@dmi.unifi.it (A.L. Zignego). 0098-2997/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2007.09.017 86 A. Craxı̀ et al. / Molecular Aspects of Medicine 29 (2008) 85–95 2.2. Malignant lymphoproliferative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.3. Other extrahepatic disorders and overlapping syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 1. Introduction Chronic hepatitis C virus (HCV) is among the most common viral infections causing major human chronic pathology worldwide (Shepard et al., 2005). Some large nations in the developed world have relatively low rates of seroprevalence of HCV, including Germany (0.6%) (Palitzsch et al., 1999), Canada (0.8%) (Zou et al., 2000), France (1.1%) and Australia (1.1%) (Australian census, 2001; Law et al., 2003). Low, but slightly higher seroprevalence rates have been reported in the USA (1.8%) (Alter et al., 1999), Japan (1.5–2.3%) (Hayashi et al., 1994; Ito et al., 1991) and Italy (2.2%) (Kondili et al., 2002). At least 100,000 deaths are annually attributable to hepatitis C, directly or with the intervention of cofactors such as HBV, HIV or alcohol abuse. In the USA it is projected that hepatitis C-related deaths will triple by 2020 (Davis et al., 2003a). Chronic hepatitis C is an important and emerging factor in hepatocellular carcinoma and is now the leading indication for liver transplantation (Shuhart et al., 1997). Unfortunately, HCV infection is often underdiagnosed. More than 50% of people at the highest risk for HCV are infected yet are unaware of their disease, leading to the spread of infection and lost treatment opportunities (Kwiatkowski et al., 2002). Infection with HCV, when not cleared during its earlier phase, may lead to diverse clinical manifestations, most often but not exclusively centred upon the liver. This review aims to briefly review the natural course of HCV infection and liver disease, and then focus on its expression at extrahepatic sites. 1.1. Natural course of HCV infection Among the subjects exposed to HCV, 15–40% clear the infection within 6 months (Alter et al., 1992; Jauncey et al., 2004). The remaining 60–85% of patients who still had detectable HCV RNA for 6 months are considered to be chronically infected (Nguyen et al., 1996). Up to 30% of chronically infected patients had persistently normal alanine aminotransferase (ALT) levels (Bruce et al., 2006). As a result, ALT levels and a positive HCV serology result are not adequate for the diagnosis of chronic HCV infection. The detection of HCV RNA is required to establish a diagnosis of active HCV infection. Results from longitudinal viremia studies have indicated that spontaneous resolution of chronic HCV infections occurs at a rate of 0.50–0.74% per person-year annually (Scott et al., 2006; Watanabe et al., 2003). On the other side, at least 20% of individuals with chronic hepatitis C eventually develop liver cirrhosis, which may be complicated by hepatocellular carcinoma, hepatic decompensation, or death (Lauer and Walker, 2001). Most patients develop asymptomatic infection but will often have high-level viremia and elevated ALT levels in the acute infection period. Hepatitis C virus (HCV) RNA can be detected 1–3 weeks after infection, approximately 1 month before the appearance of antibodies. If HCV RNA is still detectable after 6 months, the patient is considered to be chronically infected and the HCV RNA level will remain more or less stable (within 0.5 log) (Chevaliez and Pawlotsky, 2007; Scott and Gretch, 2007). 1.2. HCV RNA testing Nucleic acid tests (NATs) directly detect the presence of HCV RNA using a combination of amplification and detection techniques. Nucleic acid tests are classified into qualitative tests (qualitative polymerase chain reaction [PCR], transcription-mediated amplification [TMA]), and quantitative tests (branched-chain DNA [bDNA] amplification, quantitative PCR, and real-time PCR). Guidelines covering the indications, interpretation, and recommended tests have recently been reviewed by Scott and Gretch (Scott and Gretch, 2007). In general, NATs are quite sensitive and specific. A negative NAT result following a positive serological test result is usually indicative of a resolved infection. However, intermittent or low-level viremia may occur during A. Craxı̀ et al. / Molecular Aspects of Medicine 29 (2008) 85–95 87 chronic infection (Scott et al., 2006), and for this reason a second NAT should be performed 6–12 months later. In addition, those patients with ongoing exposure to HCV can be reinfected. A positive HCV NAT result indicates active infection regardless of antibody test results. In acute infections, as in occupational exposures, the NAT result will become positive within 1–3 weeks, several weeks earlier than serological tests. Alberti and colleagues (Alberti et al., 1992) demonstrated that detection of HCV RNA in serum is the definitive marker of hepatitis C liver disease regardless of ALT levels. Thus, documentation of HCV viremia is the hallmark of HCV diagnostics in antibody-positive and in HCV antibody-negative patients with unexplained ALT elevations or liver disease documented by liver biopsy (Gretch, 1997). Early clinical trials of interferon (IFN)-based antiviral regimens showed that patients with a baseline HCV RNA level of more than 2 million copies/mL had a 9% lower sustained virological response (SVR) rate than those with less than 2 million copies/mL (McHutchison et al., 1998). Using the World Health Organization international standard, it was determined that 800 000 IU/mL corresponds to 2 million copies/mL. By the extrapolation of these findings, a high viral load is considered greater than 800 000 IU/mL and a low viral load is defined as less than 800 000 IU/mL (Pawlotsky et al., 2000). Further studies have found that patients with low HCV RNA levels had a 15–39% better response rate than those with high HCV RNA levels, a finding that is consistent across trials using different formulations and dosages of interferon (Manns et al., 2001; Trabaud et al., 1997). The rate of virological response has become the leading parameter to monitor during the treatment of chronic hepatitis C. Sustained virological response is defined as testing negative for HCV RNA 6 months after the cessation of therapy, and is the gold standard for treatment response. Monitoring changes in HCV viral load after 4 and 12 weeks of therapy predicts the likelihood of SVR (Davis et al., 2003b; Fried et al., 2002; Jensen et al., 2006). Patients who test negative for HCV RNA at 4 weeks are defined as having a rapid virological response (Davis et al., 2003b; Ferenci et al., 2005) and those who test negative at 12 weeks are defined as having an early virological response. For patients infected with genotype 1 HCV whose HCV RNA levels have not declined by at least two logs after 12 weeks of therapy, the chance of sustained virological response is 0–3% and cessation of therapy should be considered. Compared with week-12 testing, week-4 viral load testing provides slightly better positive predictive value (75% vs 67%) (Ferenci et al., 2005). Several recent studies have challenged the conclusion that HCV is truly eradicated after a documented sustained virological response. In one study, researchers detected HCV RNA in 15 of 17 serum samples and in 9 of 12 samples of peripheral blood mononuclear cells (PBMC) taken from patients previously reported as having tested negative for HCV RNA after either spontaneous or treatment-induced resolution (Berg et al., 2006). A second research group reported the frequent detection of HCV RNA in liver biopsies and PBMC from patients with abnormal liver function tests whose serum sample tested negative for HCV antibody and RNA (Marcellin et al., 1997), leading to speculation of a new clinical entity designated as occult hepatitis C. A study of patients who tested positive for HCV antibodies but negative for HCV RNA with normal serum ALT levels found that 10 of 12 patients had HCV RNA in liver biopsies (Radkowski et al., 2005). Because of the technical difficulties in evaluating HCV replication ex vivo, the possibility of reinfection and the controversies in the literature, additional rigorous studies are needed to confirm these reports of occult HCV infection, both during natural infection and after therapy. 1.3. Extrahepatic conditions linked to HCV infection HCV infection has been associated with numerous extrahepatic manifestations (EHMs-HCV) (Cacoub et al., 1999; Zignego and Brechot, 1999). The list of diseases suggested or proven to be related to HCV is theoretically wide, ranging from EHMs-HCV characterized by a very strong association – proven by both epidemiological and pathogenetic evidence – and disorders for which a significant association with HCV infection is supported by substantial data to associations that still require confirmation or only anecdotal observations (Table 1, Zignego et al., 2007a). Actually, most reports are still based on a relatively small number of patients, inappropriate controls or patient selection bias. Antiviral therapy is now considered the first choice treatment for most EHMs-HCV, however, in some cases IFN was ineffective or dangerous. B-cell lymphoproliferative disorders (LPDs), whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated EHMs-HCV and they will be more diffusely described in the present review. 88 A. Craxı̀ et al. / Molecular Aspects of Medicine 29 (2008) 85–95 2. Lymphoproliferative disorders 2.1. Mixed cryoglobulinemia Mixed cryoglobulinemia (MC) is a non-neoplastic B-cell LPD representing the most common EHMs-HCV (Ferri et al., 1993b; Misiani et al., 1992; Zignego et al., 1997). Cryoglobulins (CGs) are serum immunoglobulins (Igs) that reversibly precipitate below 37 °C during blood tests. According to Brouet et al. (Brouet et al., 1974), mixed CGs are composed of a mixture of polyclonal IgG and monoclonal IgM (type II MC) or polyclonal IgM with rheumatoid factor (RF) activity (type III MC). By contrast, type I CGs are composed of a unique monoclonal component, usually sustained by an indolent B-cell lymphoma. The strong association between HCV and MC has been confirmed by serological and molecular investigations (Agnello et al., 1992; Misiani et al., 1992; Zignego et al., 1997). Different prevalence of serum CGs – ranging from 19 to >50% – have been reported in HCV patients (Lunel et al., 1994). The difficulty in a correct determination of the presence of CGs, due to their thermolability, should account for an underestimation of such phenomenon. Several studies showed that a B-cell clonal expansion (in particular of RF B-cells) underlies MC (Magalini et al., 1998; Sansonno et al., 1998), that this condition is associated with Bcl2/JH rearrangement, and that MCII can evolve into a frank B-cell non-Hodgkin’s lymphoma (NHL) in approximately 8–10% of cases (Ferri et al., 1994d; Ferri et al., 2004). A monoclonal lymphoproliferation of uncertain significance (MLDUS) in liver and bone marrow infiltrates is a typical feature of subjects with clinico-laboratory features of MC-II (Ferri et al., 2000; Ferri et al., 2006; Zignego et al., 2007a). MC clinical manifestations are secondary to a systemic vasculitis – involving medium and, more often, small sized blood vessels – that is responsible for MC tissue injury. Such vasculitis is probably secondary to the vascular deposition of circulating immune complexes (CIC), mainly CGs, and complements, with the possible contribution of both haemorheological and local factors (Ferri et al., 2002b; Gorevic et al., 1980). MC-related symptoms are generally absent or very mild, whereas clinically evident MC – MC syndrome or MCS – would be evident in 10–15% to 30% of MC subjects and in 5–10% of all HCV infected patients (Lunel et al., 1994). No standardized criteria are at present available for the diagnosis of MCS even if valuable classifications have been proposed (Ferri et al., 2002b). The most common symptoms of MCS are weakness, arthralgias, and palpable purpura that usually involves the lower extremities (Meltzer and Franklin triad). Different clinical manifestations include Raynaud’s phenomenon, peripheral neuropathy, sicca syndrome, membranoproliferative glomerulonephritis (MPGN), as well as lung disorders, fever, hematocytopenia, and diffuse vasculitis. (Ferri et al., 2004; Zignego et al., 2007b). Circulating mixed CGs, low C4, and orthostatic skin purpura are the hallmarks of the disease. Given its clinical polymorphism, the presentation of MCS may greatly vary in different subjects and in the same patient at different times. Consequently, the actual prevalence of MCS is probably underestimated. A peripheral neuropathy is the most common complication of MC, ranging from 7 to 80–90% of cases (Ferri et al., 1992; Zignego et al., 2007b). The presence of a renal involvement is one of the worst prognostic indices in the natural history of MCS, even if its course can be variable (Ferri et al., 2004; Zignego et al., 2007b). Several studies have shown an epidemiological association between MC and severe liver damage (Kayali et al., 2002; Lunel et al., 1994). An association between MC and liver steatosis was also suggested (Saadoun et al., 2006). The current treatment strategy of HCV-associated MC includes targeting the viral trigger HCV with antiviral treatment or the downstream pathogenetic events by means of various combinations of antiphlogistic and immunosuppressive drugs as well as methods able to favor the endogenous or mechanical clearance of CIC (Zignego et al., 2007b). Recently, traditional immunosuppressive therapy of MC has been enriched by the introduction of Rituximab, a chimeric monoclonal anti-CD20 antibody which has been proven to be useful in improving most clinical manifestations and B-cell lymphoproliferation in the majority of MC patients (Sansonno et al., 2003; Zaja et al., 2003). Its possible enhancing effect on HCV replication should represent a major hurdle suggesting the opportunity of a combination with antiviral therapy (Fig. 1). 89 A. Craxı̀ et al. / Molecular Aspects of Medicine 29 (2008) 85–95 Therapy of HCVHCV-related MCS Assessment of MCS and of contraindications to IFNIFN-based therapy Contraindications to IFN and/or severe MCS No contraindications and mild/moderate MCS Moderate-severe MPGN, skin vasculitis or Severe-rapidly progressive MPGN Severe sensomotor neuropathies Widespread vasculitis Mild-moderate purpura Weakness Arthralgias Mild neuropathy PEG IFN plus ribavirin* Rituximab LAC diet Low-medium doses CS +/- other symptomatics MCS RESPONDERS MCS NON RESPONDERS PE + CS +/- CF se ve re NON RESPONDERS RESPONDERS * Schedule as for non-MC patients Antiviral therapy ? Fig. 1. Algorithm for the treatment of HCV-positive mixed cryoglobulinemia patients. Available data suggest that antiviral therapy should be considered as the first choice treatment in mixed cryoglobulinemia and that combined pegIFN and ribavirin therapy is the most effective one. Accordingly, an accurate clinical evaluation of MC patients is requested to evaluate the existence of known contraindications to IFN and RBV, as well as to evaluate the severity of MCS. A cautious attitude is recommanded in case of severe manifestations such as acute nephritis or widespread vasculitis. When antiviral treatment is not indicated this algorithm suggests other approaches for the management of mixed cryoglobulinemia, including anti-inflammatory drugs (first corticosteroids – CS –), procedures able to lower the concentration of cryoglobulins such as the low antigen content (LAC) diet or plasma exchange (PE) as well as immunosuppressive drugs (cyclophosphamide – CF –). In patients with only mild to moderate syndrome, cycles of therapy with anti-inflammatories, the LAC diet or other symptomatic treatments are suggested. Therapy should be adapted to the single patient and limited in time. In patients with more severe syndromes, cycles of plasma exchange plus corticosteroids and/or immunosuppressive drugs are indicated. Rituximab, a selective B-cell suppressor, has proven to be efficacious in some cases where antiviral therapy was initially contraindicated; its usefulness also in different conditions is under investigation. Concerning the antiviral (etiologic) therapy, initial studies utilizing IFN monotherapy, showed the efficacy of such treatment on most MCS cases, even with almost constant virological relapse after therapy interruption (Zignego et al., 2007b). Clinical and virological response were closely associated in most cases. The mean prevalence of sustained response progressively increased from 12.5% using IFN monotherapy, to 39.7% with a combination of IFN plus RBV regimens, and up to 63% using combined PEG IFN plus RBV therapy (Ferri et al., 1993a; Ferri et al., 1993c; Johnson et al., 1993). In addition, a sustained clinical response was confined to MCS cases who completely cleared the virus. In spite of the need for larger, controlled studies and follow-up, available data strongly suggest that HCV eradicating therapies should be considered as the first line therapeutic approach in MCS patients. However, with multiorgan involvement, the antiviral therapy may be limited due to the severity of renal disease, treatment failure, side effects or contraindications. A possible therapeutic algorithm for HCV MC patients is outlined in Fig. 1. However, any attempt to trace a guideline for MCS treatment must take into account the complexity of such systemic disorder and the wide range of possible clinical presentations, strongly recommending an individualized tailoring of therapy and follow-up. 90 A. Craxı̀ et al. / Molecular Aspects of Medicine 29 (2008) 85–95 On the whole, results of antiviral therapy were of critical importance for the development of pathogenetic hypotheses. As an example of this, it was observed that expanded B cell clones harboring the (14;18) translocation (bcl-2 rearrangement) – a frequent finding in HCV MC – regressed after virological response and could expand again following virological relapse (Giannelli et al., 2003; Zignego et al., 2002; Zignego et al., 2000). The critical role played by viral replication was confirmed by the persistence of clinical stigmata of MCS in patients with only apparent viral clearance but maintaining HCV occult lymphatic infection (Giannini et al., 2006). Actually it may be suggested that HCV chronic infection – particularly of lymphatic cells – may induce a sustained and strong B cell polyclonal activation through different host and virus-related mechanisms. This may favor successive mutational events which may drive the LPD toward the independence from the initial event (HCV infection). A more direct action of HCV in inducing mutagenetic events has been also suggested (Machida et al., 2004). In MC patients, a particular involvement of certain RF producing B-cells may be envisaged. Apart from this particular condition, the combination of persistent B-cell activation and anti-apoptotic mechanisms acting on B cells is recognized as a condition favoring lymphomagenesis (Zignego et al., 2007b). The existence of points of no return in the natural history of MCS seems to be confirmed by the sporadic observation of patients with long lasting severe syndrome maintaining MCS stigmata after successful antiviral therapy and without evident or occult HCV persistence (Giannini C, personal communication). In turn, such observations strongly suggest the need for an early HCV eradicating therapy. 2.2. Malignant lymphoproliferative disorders Increasing evidence points toward a role of HCV infection in the etiology of malignant lymphomas. HCVassociated lymphatic malignancies may be observed during the course of MC, as cited above, or as idiopathic forms (Zignego et al., 2007b). A significant association between B-cell derived NHL and HCV infection was initially reported in limited Italian surveys (Ferri et al., 1994a,b,c; Luppi et al., 1996; Silvestri et al., 1996), and subsequently confirmed by the large majority of international studies (Ferri et al., 2000; Luppi et al., 1996; Matsuo et al., 2004; Mele et al., 2003), in spite of some discordant data obtained in northern European and North American studies. Actually, in analogy with what is observed in epidemiological studies focusing on association between HCV and MC, a clear south/north gradient of prevalence exists, in part reflecting different HCV infection prevalence in the general population, and suggesting the contribution of environmental and/or genetic factors (Matsuo et al., 2004). B-cell-derived NHL represents the great majority of HCV-related lymphatic malignancies (De Vita et al., 1997; Ferri et al., 1994b; Ferri et al., 2000; Luppi et al., 1996; Luppi et al., 1998), the most frequently described histotypes being peripheral B-cell-derived indolent NHL (Luppi et al., 1998; Talamini et al., 2004; Ferri et al., 2000; Luppi et al., 1998). A more specific association has been recently suggested for splenic lymphoma with circulating villous lymphocytes – as confirmed by hematological regression after antiviral therapy (Hermine et al., 2002; Saadoun et al., 2005) – and diffuse large B cell lymphoma (Nieters et al., 2006). A serum monoclonal gammopathy, more frequently of MGUS (monoclonal gammopathies of uncertain significance) type, was also included among HCV-associated LPDs (Andreone et al., 1998). The demonstration of the regression of clonal proliferation in response to effective antiviral treatment clearly suggests the rationale for the use of antiviral therapy in malignant LPDs (Giannelli et al., 2003; Zignego et al., 2002; Zuckerman et al., 2001). Unfortunately, only some lymphomas can be cured with antiviral therapy. In addition, it has been observed that, even in cases of responsive SLVL, the rearrangement of the monoclonal Ig genes was still detectable in the blood (Saadoun et al., 2005), confirming the hypothesis of points of no return in the multi-step lymphomagnetic cascade, making LPD more and more independent of HCV infection. Although antiviral therapy appears to be an attractive therapeutic tool for low-grade HCV-positive NHL, in intermediate and high-grade NHL, chemotherapy is expected to be necessary and antiviral treatment may be suggested as maintenance therapy after chemotherapy completion. Further studies are needed to better standardize the antiviral therapy for HCV-related NHL patients. 2.3. Other extrahepatic disorders and overlapping syndromes Several different disorders have been observed in association with HCV infection. In the majority of cases, because of possible methodological bias, mainly in patient selection among different studies, it is difficult to A. Craxı̀ et al. / Molecular Aspects of Medicine 29 (2008) 85–95 91 verify whether the suggested association is coincidental or whether a pathogenetic link really exists. In addition, a clinicoserological overlap between different EHMs-HCV could be observed with some frequency (Ferri et al., 1998; Ferri and Zignego, 2000; Ferri et al., 2002b). In particular, several disorders are more frequently observed in the context of a MCS and quite rarely as idiopathic forms. It is the case, for instance, of skin, kidney, salivary glands or lung disorders. On the whole, in the same patient, it is possible to evidence a varying combination of both hepatic and extrahepatic disorders generally based on autoimmune/lymphoproliferative nature. These observations support the opportunity that HCV infection may be always seen as a distinct systemic disease with variable clinical expression (Zignego et al., 2007b). Among non-MCS-related EHMs-HCV a strong association with HCV infection was suggested for the sporadic variant of porphyria cutanea tarda as well as for oral lichen planus (Cribier et al., 1994). However, it is generally admitted that in these cutaneous disorders HCV infection plays a role of triggering factor in genetically predisposed subjects. As a matter of fact, attempts to cure these disorders with antiviral therapy led to discordant, but generally negative results, with the possible induction of a clinical manifestation in previously unaffected patients or aggravation of the disease (Zignego et al., 2007b). Neurologic disorders as well as nephropathies have been associated with HCV infection also in the absence of MC (Agnello et al., 1992; Johnson et al., 1993; Lidove et al., 2001; Pasquariello et al., 1993; Stehman-Breen et al., 1995) but, at present, only the cryoglobulinemic forms have been clearly associated with the infection. HCV-related chronic polyarthritis can be observed in HCV-positive patients both with and without MC (Ferri et al., 2004). Intermittent oligoarthritis, generally not erosive and involving the big and middle articulations, is frequently observed (Ferri et al., 2004). A Sjögren-like syndrome is frequently observed in HCV-positive patients, mainly in the context of MC (Haddad et al., 1992; Meltzer et al., 1966). HCV infection has been suggested to represent a criterion to exclude diagnosis of primary Sjögren syndrome, especially if CGs and hypocomplementemia are present, and anti-SSA/Ro antibodies absent. A high prevalence of diabetes mellitus type 2 was observed in patients with chronic HCV infection in several studies (Antonelli et al., 2005; Knobler et al., 2000), and it has been suggested that HCV acts as a risk factor independent of liver disease. In patients with HCV infection, the appearance of diabetes type 2 was associated with high insulin-resistance and was considered a part of a complex virus-induced dysmetabolic syndrome including both hepatic (steatosis) and extrahepatic manifestations. In agreement with this, an association between aortic atherosclerosis and HCV infection has been recently suggested (Boddi et al., 2007; Ishizaka et al., 2002). The association between HCV infection and hypertrophic cardiomyopathy and dilatative cardiomyopathy was also suggested. Additional suggested associations include thyroid disorders, erectile dysfunction (Ferri et al., 2002a) and psychopathological disorders (Dwight et al., 2000; Forton et al., 2002; Zignego et al., 2007b). 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