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Abstract

During hepatitis C virus (HCV) chronic infection, extrahepatic manifestations are frequent and polymorphous. This article reports on a large cohort of patients with HCV-related autoimmune or lymphoproliferative disorders, from mixed cryoglobulinemia vasculitis to frank lymphomas. The relationship between HCV infection and such immune-related diseases has been formally demonstrated by epidemiological, clinical, immunological and pathological data, and results of therapeutic trials. More recently, other nonliver-related HCV disorders have been reported, including cardiovascular (i.e. stroke, ischemic heart disease), renal, metabolic and central nervous system diseases. For these manifestations, most evidence comes from large epidemiological studies; there is a need for mechanistic studies and therapeutic trials for confirmation. Beyond the risk of developing liver complications, that is, cirrhosis and liver cancer, patients with HCV infection have an increased risk of morbidity and mortality related to nonliver diseases. HCV chronic infection should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. The need for effective viral eradication measures is underlined.

Keywords

extrahepatic manifestations hepatitis C virus treatment

Hepatitis C virus (HCV) infection is a major health problem with 150–170 million people chronically infected. On the one hand, these patients are at risk of developing liver complications, that is, cirrhosis and liver cancer, with an estimated liver-related mortality of 350,000 people/year. On the other hand, in large cohort studies, two-thirds of patients with HCV infection experienced extrahepatic manifestations [Cacoub et al. 1999]. Some of these conditions are well documented and more common, while others are infrequent [Cacoub et al. 2000; Zignego et al. 2007; Zignego and Bréchot, 1999]. Soon after HCV discovery, HCV-related autoimmune or lymphoproliferative disorders, from benign mixed cryoglobulinemia to frank lymphomas, have been reported [Zignego et al. 2007; Terrier et al. 2013; Sene et al. 2004]. More recently, many other nonliver HCV-associated disorders have been reported, including cardiovascular, renal, metabolic and central nervous system diseases (Table 1). HCV infection showed a higher mortality rate for extrahepatic complications [Lee et al. 2012; Maasoumy and Wedemeyer, 2012; Omland et al. 2011; Uto et al. 2009]. All-cause mortality in patients with HCV was increased more than twice compared with patients without HCV [El-Kamary et al. 2011], probably related to serum HCV RNA positivity [Lee et al. 2012]. Viral eradication significantly reduced the rate of extrahepatic deaths [Adinolfi et al. 2014; Backus et al. 2011; Hsu et al. 2014; Kawamura et al. 2007]. Recent therapeutic advances in the treatment of HCV, with the possibility to eradicate HCV following new direct antiviral therapies appears of major importance, for liver and nonliver manifestations of the disease.

Table 1.

Main extrahepatic manifestations in patients with hepatitis C virus infection.

Immune-related extrahepatic manifestations

Mixed cryoglobulinemia

Cryoglobulinemic vasculitis

B-cell NHL

Sicca syndrome

Arthralgia/myalgia

Autoantibody production (i.e. cryoglobulins, rheumatoid factor, and antinuclear, anticardiolipin, antithyroid and anti-smooth muscle antibodies)

Polyarteritis nodosa

Monoclonal gammopathies

Immune thrombocytopenia

Inflammatory-related extrahepatic manifestations

Type 2 diabetes mellitus type 2

Insulin resistance

Glomerulonephritis

Renal insufficiency

Fatigue

Cognitive impairment

Depression

Impaired quality of life

Polyarthritis/fibromyalgia

Cardiovascular disorders (i.e. stroke, ischemic heart disease)

NHL, non-Hodgkin’s lymphoma.

Cryoglobulinemia vasculitis

Mixed cryoglobulinemia (MC) vasculitis (Cryovas) is a small vessel vasculitis involving mainly the skin, the joints, the peripheral nerve system and the kidneys [Terrier et al. 2013]. HCV infection is the cause of Cryovas in about 80% of cases. The disease expression is variable, ranging from mild symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). Skin is the most frequently involved target organ: palpable purpura, chronic cutaneous ulcers, Raynaud’s phenomenon, acrocyanosis, which may evolve to digital ulcerations. Neurologic manifestations range from pure sensory axonopathy to mononeuritis multiplex. The most frequent form is a distal sensory or sensory-motor polyneuropathy, presenting with painful, asymmetric paresthesia. Less frequently, multiple mononeuropathy may occur. Renal involvement is an acute or chronic type I membranoproliferative glomerulonephritis with subendothelial deposits, strongly associated with the type II immunoglobulin Mκ (IgMκ) MC. The usual presentation is proteinuria with microscopic hematuria and a variable degree of renal insufficiency. Cryoglobulinemia is confirmed by the detection of protein precipitates in the patient’s serum maintained at 4℃ during at least 7 days, which dissolved at 37℃. HCV MC are characterized as type II or type III cryoglobulins which consist of polyclonal IgG with monoclonal or polyclonal IgM with rheumatoid factor (RF) activity, respectively [Sène et al. 2004]. During follow up, biological improvement can be assessed by the quantification of cryoglobulinemia and other surrogate markers (C4, CH50, RF).

During HCV infection, Cryovas is associated with advanced age, longer duration of infection, type II MC, a higher MC serum level and clonal B-cell expansions in both the blood and liver. The worse prognostic factors are an age greater than 60 years at diagnosis and renal involvement [Terrier et al. 2011]. The overall 5-year survival rate after the diagnosis of Cryovas ranges from 90% to 50% in the case of renal involvement. Increased mortality from liver involvement, cardiovascular disease, infection and lymphoma has been reported. In a retrospective Italian study of 231 patients, 79/97 deaths were linked to vasculitis (46%, of which one-third were due to renal involvement), cancer or hemopathy (23%), or liver disease (13%) [Ferri et al. 2004]. Cryovas complications may result in progressive (renal involvement) or acute (pulmonary hemorrhage, gastrointestinal ischemia, cardiac, central nervous system involvement) life-threatening organ damage, with a mortality rate between 20% and 80% [Retamozo et al. 2013; Terrier et al. 2013]. Intestinal ischemia, pulmonary hemorrhage, high cryocrit levels and type II MC are associated with severe prognosis [Ramos-Casals et al. 2006].

There are multiple factors predisposing patients with HCV infection to develop Cryovas. Interaction between HCV and lymphocytes directly modulates B- and T-cell function and results in polyclonal activation and expansion of B-cell-producing IgM with RF activity [Saadoun et al. 2005a]. CD4⁺CD25⁺FoxP3⁺regulatory T cells are reduced in patients with Cryovas [Boyer et al. 2004; Saadoun et al. 2011] which may account for the expansion of peripheral autoreactive B cells that drive Cryovas. Human leucocyte antigen (HLA-DR11) is associated with Cryovas whereas HLA-DR7 appears to protect against Cryovas [Cacoub et al. 2001]. In a recent multicenter genome-wide association study significant associations were identified on chromosome 6, a single nucleotide peptide located within an intronic region of NOTCH4 (p = 6.2 × 10^–9) and another found in between HLA-DRB1 and HLA-DQA1 (p = 1.2 × 10^–7) [Zignego et al. 2014]. Specific virological factors have not yet been identified.

Most HCV-Cryovas manifestations respond to clearance of HCV during antiviral therapy with pegylated interferon (pegIFN) plus ribavirin [Saadoun et al. 2006]. Patients who have relapsed HCV infection after responding to antiviral therapy usually have relapsed Cryovas with the return of viremia [Saadoun et al. 2006]. In case of persistent MC, relapse of vasculitis might also occur despite achieving a sustained virologic response (SVR); this situation should lead to a search for a different underlying condition, especially B-cell lymphoma [Landau et al. 2008]. Recent use of triple anti-HCV therapy with pegIFN/ribavirin and a direct antiviral agent (boceprevir or telaprevir) led to improved rates of SVR and Cryovas remission in HCV genotype 1 [Gragnani et al. 2014]. Other direct-acting antivirals such as sofosbuvir and simeprevir have recently been licensed, which facilitate the use of shortened courses of combination IFN-free therapy and are associated with high (>95%) SVR rates and few toxicities. International guidelines [European Association for Study of Liver, 2014] state that treatment should be scheduled, not deferred, for patients with clinically significant extrahepatic manifestations, like Cryovas. Rituximab is an interesting therapy in MC, as it targets B cells, which are responsible for cryoglobulin production and finally Cryovas lesions. Two randomized controlled trials showed that rituximab has a better efficacy than conventional treatment (i.e. glucocorticoids, azathioprine, cyclophosphamide or plasmapheresis) [De Vita et al. 2012]. Two other controlled clinical trials showed that addition of rituximab to pegIFN/ribavirin led to a shorter time to clinical remission, better renal response rate and higher rates of cryoglobulin clearance [Dammacco et al. 2010; Saadoun et al. 2010].

In daily practice, patients with HCV Cryovas with mild to moderate disease should be given an optimal antiviral treatment. For patients with severe vasculitis (i.e. worsening of renal function, mononeuritis multiplex, extensive skin disease, intestinal ischemia etc.) control of disease with rituximab, with or without plasmapheresis, is required before initiation of optimal antiviral therapy [Saadoun et al. 2008]. Careful monitoring for adverse effects is mandatory, since some manifestations of HCV Cryovas, such as peripheral neuropathy or skin ulcers, may worsen with IFN-based therapy. Low-dose corticosteroids may help to control minor intermittent inflammatory signs, such as arthralgia, but do not succeed in the case of major organ involvement. Other immunosuppressants should be given only in the case of refractory forms of HCV Cryovas, usually associated with underlying B-cell lymphoma [Saadoun et al. 2013].

B-cell lymphoproliferative diseases

A high prevalence of HCV infection in patients with B-cell non-Hodgkin’s lymphoma (B-NHL) was reported in meta-analyses, with a gradient from north to south [Dal Maso and Franceschi, 2006; de Sanjose et al. 2008; Gisbert et al. 2003; Matsuo et al. 2004; Negri et al. 2004]. HCV was associated with marginal zone NHL [odds ratio (OR) 2.47] and diffuse large B-NHL (OR 2.24). A serum monoclonal gammopathy, more frequently IgMκ, was frequently observed [Andreone et al. 1998]. A lower cumulative incidence of lymphoma development in patients who eradicated the virus confirms this association and suggests that HCV treatment could be a preventive measure [Kawamura Y et al. 2007]. SVR-induced NHL regression, while a viral relapse, was followed by lymphoma recurrence [Saadoun et al. 2005]. HCV-positive splenic lymphoma with villous lymphocytes regressed after antiviral therapy [Hermine et al. 2002]. Regression of expanded B-cell clones following successful antiviral treatment have been reported with expansion of the same clones in virological relapsers [Giannelli et al. 2003; Zignego et al. 2002]. The same picture was shown in patients with benign lymphoproliferative conditions (i.e. type II or III MC], whereas a persistent B-cell clone despite a clinical remission was evidenced in SVRs with splenic lymphoma with villous lymphocytes [Saadoun et al. 2005b]. This leads to the concept of no-return points in HCV-driven lymphomagenesis, with a lymphoproliferation initially antigen sensitive and then antigen insensitive.

HCV-related lymphoproliferative disorders are the result of multiple and cooperating events, that is, sustained activation of B cells [Lai and Weiss, 1998; Sansonno et al. 1998; Vallat et al. 2004], inhibition of B-cell apoptosis, genetic/epigenetic and environmental factors [Landau et al. 2009; Zignego et al. 2012]. The lymphotropism agrees with a higher HCV infection prevalence in peripheral blood mononuclear cells (PBMCs) and bone marrow [Galli et al. 1995; Zignego et al. 1992] and was confirmed by in vivo and in vitro studies [Bronowicki et al. 1998; Sung et al. 2003]. HCV-infected cells showed an increased rate of mutations of oncogenes and immunoglobulin genes. Transgenic models showed a correlation between the expression of HCV core and lymphoma [Kasama et al. 2010; Tsukiyama-Kohara et al. 2011]. The t(14;18) translocation causes increased Bcl-2 levels and abnormal B-cell survival [Zignego et al. 1997, 2000, 2002] and disappear after antiviral treatment [Giannelli et al. 2003; Giannini et al. 2006, 2008]. The role of cytokines and chemokines has been studied [Libra et al. 2005, 2006; Saadoun et al. 2005a, 2007; Sansonno et al. 2009], with special attention of the B-cell activating factor [De Vita et al. 2008; Landau et al. 2009; Sène et al. 2007].

Treatment of HCV-positive lymphoma with antiviral treatment should lead to the eradication of the etiologic factor. A clinical remission following antivirals was shown in low-grade B-NHL, mainly marginal zone lymphoma [Arcaini et al. 2014; Hermine et al. 2002; Kelaidi et al. 2004; Mazzaro et al. 2009; Saadoun et al. 2005b; Vallisa et al. 2005]. IFN-based treatment showed an improved overall survival in patients with indolent HCV-associated NHL [Arcaini et al. 2014]. Antivirals following NHL remission showed improved clinical outcome and prolonged disease-free survival [La Mura et al. 2008; Musto et al. 1996]. The use of rituximab in HCV-NHL, alone or in combination with antivirals or chemotherapy, appears interesting in low-grade NHL [Hainsworth et al. 2002; Saadoun et al. 2010].

Arthralgia/myalgia

Arthralgia is reported in 40–80% of patients with HCV infection [Cacoub et al. 2000; Lee et al. 1998]. Patients present with symmetric joint pains, nondeforming, involving mainly knees and hands. HCV arthritis is less common. RF activity is found in 70–80% of patients with MC but it is not correlated with the presence of joint disease. Antibodies to cyclic citrullinated peptide are absent. Some treatment modalities for HCV infection, including IFN, may aggravate arthralgia and myalgia, thus confounding clinical presentation. It is imperative to distinguish whether symptoms such as arthralgia, myalgia and arthritis occurring in patients with HCV infection are related to chronic HCV infection or to a newly developed rheumatologic disease.

Sicca syndrome

Sicca symptoms of either the mouth or eyes have been reported in 20–30% of patients with HCV infection, whereas less than 5% of patients with Sjögren’s syndrome are HCV positive [Cacoub et al. 2000]. Many similarities exist between HCV-related sicca syndrome and ‘true’ Sjögren’s syndrome [Ramos-Casals et al. 2001]. However, a characterized Sjögren’s syndrome defined by the presence of xerostomia, xerophthalmia, anti-SSA or anti-SSB antibodies and typical salivary gland histology is rarely found in patients with HCV infection. Patients with HCV-positive Sjögren’s syndrome are older and more likely to have photosensitivity and cryoglobulinemia than patients with primary Sjögren’s syndrome. Low titers of antinuclear antibodies and RF are common in patients with HCV-related sicca syndrome but the presence of Sjögren’s syndrome related autoantibodies (anti-SSA/SSB antibody) is uncommon. The expression of HCV E1 and E2 glycoproteins in transgenic mice is associated with the development of sialadenitis [Koike et al. 1997].

Autoantibodies

Biological immunologic abnormalities are frequent, including mixed cryoglobulins (60–90%), RF activity (70%), and antinuclear (20–40%), anticardiolipin (15%), antithyroid (12%) and anti-smooth muscle antibodies (7%) [Cacoub et al. 1999; Cacoub et al. 2000]. These autoantibodies however are not associated with manifestations of a connective tissue disease except for mixed cryoglobulins. Reported underlying mechanisms include HCV-induced overactivation and proliferation of B lymphocytes.

Cardiovascular diseases

Asian studies suggest an association between HCV infection and an increased risk of carotid artery plaques and carotid intima media thickening, independently of classical cardiovascular risk factors [Fukui et al. 2003]. Patients with HCV infection showed a higher likelihood of having carotid atherosclerotic plaques compared with HCV-negative controls [Aslam et al. 2010], particularly in those with active viral replication. Suggested mechanisms include the production of proatherogenic cytokines [Adinolfi et al. 2014]. Other studies performed in patients with HCV or coinfected with HCV and human immunodeficiency virus (HIV) confirmed the link between HCV infection and carotid atherosclerosis [Adinolfi et al. 2012; Petta et al. 2012; Sosner et al. 2012]. Furthermore, retrospective cohort studies suggest a beneficial effect of antivirals on the incidence of stroke in patients with HCV infection [Hsu et al. 2013]. A prospective study conducted in three groups of patients with diabetes followed over 8 years showed a decreased cumulative incidence of ischemic stroke in treated versus nontreated patients with HCV infection [Hsu et al. 2014].

HCV chronic infection was shown to increase the risk of coronary artery disease, after adjustment for classical cardiovascular risk factors [Butt et al. 2009]. Patients who were anti-HCV positive had higher mortality rates from cardiovascular diseases compared with HCV-negative controls [hazard ratio (HR) 1.50; 95% confidence interval (CI) 1.10–2.03] [Lee et al. 2012]. Patients with positive viremia showed higher rates of deaths, while patients who were HCV RNA negative had rates similar to controls. A large Asian study analyzed 1411 subjects with HCV and diabetes mellitus treated with pegIFN plus RBV who were matched with 1411 patients who were HCV positive and had diabetes and were not treated with antivirals, and with 5644 patients who were HCV negative and had diabetes [Hsu et al. 2014]. After an 8-year median follow up, the cumulative incidence of death significantly decreased from untreated to treated (23.6% versus 13.0%). The incidences of end-stage renal disease, ischemic stroke and acute coronary syndrome were lowest in the cohort of patients with HCV who were treated versus those with HCV who were untreated. In addition, Maruyama and colleagues showed an improvement in the myocardial perfusion defect after antiviral treatment in patients who showed a SVR compared with those who had relapsed infection [Maruyama et al. 2013].

Renal insufficiency

Type I membrano-proliferative glomerulonephritis associated with MC is the most common form of kidney disease associated with HCV infection. Patients present with a clinical and histological picture of HCV Cryovas that is an acute or chronic type I membrano-proliferative glomerulonephritis with subendothelial deposits, with type II IgMκ cryoglobulinemia [Terrier and Cacoub, 2013]. The most frequent presentation is proteinuria with microscopic hematuria and a variable degree of renal insufficiency. Acute nephrotic or nephritic syndrome can also reveal Cryovas renal involvement, with frequent new onset arterial hypertension. Early serum complement components (C1q, C4) are very low. Chronic renal insufficiency may develop in 10–20% of patients with HCV Cryovas. Renal morphological features are characterized by important monocyte infiltrates with double contours of the basement membrane, large, eosinophilic and amorphous intraluminal thrombi. Vasculitis of small renal arteries or extracapillary crescents are rarely observed. Immunofluorescence studies show intraglomerular subendothelial deposits of IgG, IgM and complement components. The electron microscopic features with subendothelial and intraluminal deposits presenting a crystalloid aspect are pathognomonic.

There is some evidence of the association between HCV and other glomerular diseases [Fabrizi et al. 2002]. A large case–control study, carried out among US male veterans hospitalized between 1992 and 1999 [El-Serag et al. 2002], identified 34,204 patients who were hospitalized with HCV infection (cases) and 136,816 randomly selected patients without HCV infection (controls). There was a greater proportion of membrano-proliferative glomerulonephritis among patients with HCV infection (0.36% versus 0.05%, p < 0.0001). HCV infection was associated with a 40% higher prevalence of renal insufficiency compared with subjects without HCV infection, after adjusting for age, sex, race, diabetes and hypertension [Dalrymple et al. 2007]. Some large surveys have suggested an impact of HCV infection on prevalence and incidence of kidney disease in the general population [Asrani et al. 2010; Butt et al. 2011; Dalrymple et al. 2007; Lee et al. 2010; Tsui et al. 2006]. Anti-HCV status was associated with low glomerular filtration rate (OR up to 2.80) and with proteinuria (OR 1.14–1.99) [Butt et al. 2011; Huang et al. 2006; Lee et al. 2010; Liangpunsakul and Chalasani, 2005; Wyatt et al. 2008], independently of common metabolic factors, such as diabetes mellitus, arterial hypertension, obesity and dyslipidemia. In a recent population-based cohort, among 2,267,270 Taiwanese residents diagnosed with diabetes mellitus [Hsu et al. 2014], three groups were analyzed: 1411 patients with HCV infection who received pegIFN plus ribavirin (treated cohort), 1411 untreated controls with HCV infection and 5644 patients with diabetes who were HCV negative (uninfected cohort). The 8-year cumulative incidence of end-stage renal disease in the treated, untreated and uninfected cohorts were 1.1% (95% CI 0.3–2.0%), 9.3% (5.9–12.7%) and 3.3% (2.3–4.3%), respectively (p < 0.001). Antiviral treatment was associated with an HR of 0.16 (0.07–0.33%) for end-stage renal disease.

The Kidney Disease: Improving Global Outcomes (KDIGO) group recommends that all patients with chronic kidney disease should be tested for HCV [KDIGO, 2008]. KDIGO also recommends that patients with acute flares of HCV Cryovas and membrano-proliferative glomerulonephritis be treated with IFN-based therapy. Ribavirin dosage should be closely monitored due to the risk of anemia and it should be avoided in patients with chronic kidney disease. Patients with HCV Cryovas and kidney involvement showed greater renal response rates when treated with a combination of rituximab and pegIFN plus ribavirin compared with pegIFN and ribavirin alone. Of note, all these pictures should change rapidly with the use of new direct-acting anti-HCV treatments.

Insulin resistance and type 2 diabetes

Insulin resistance (IR) is a frequent condition, coexisting with obesity and metabolic syndrome, possibly evolving to type 2 diabetes. In a small cohort of patients treated with anti-HCV therapy, Taskoparan and colleagues failed to establish a correlation between IR and chronic HCV infection [Taskoparan et al. 2011]. The presence of IR was evaluated in patients with HCV achieving a SVR after pegIFN plus ribavirin. On the one hand, the treatment response was not impaired by IR. On the other hand, treatment failure and high body mass index were independent risk factors for de novo appearance of IR after treatment. No new IR cases were registered in patients with SVR, suggesting that HCV eradication could prevent IR onset and its evolution to diabetes [Aghemo et al. 2012]. Insulin resistance has been shown to impair SVR rate to pegIFN plus ribavirin in patients coinfected with HIV and HCV [Cacoub et al. 2009].

HCV-related type 2 diabetes mellitus may arise from a complex interaction between IR, steatosis and inflammatory processes [Serfaty and Capeau, 2009]. Epidemiologic studies supporting the association between type 2 diabetes and HCV infection have been published in the early 1990s. In larger epidemiologic studies [Caronia et al. 1999; Mason et al. 1999], the prevalence of diabetes was higher in HCV- than in HBV-related cirrhosis [23.6% versus 9.4%; OR 2.78 (95% CI 1.6–4.79); p = 0.0002]. Diabetes was associated with the presence of cirrhosis and male sex. An epidemiologic study conducted in Egypt in a pediatric population of 150 patients with type I diabetes revealed a prevalence of HCV infection higher than in controls [Farghaly et al. 2014].

Fatigue, depression and cognitive impairment

Neurocognitive morbidity in patients with HCV infection does not completely correlate with the severity of liver disease [Forton et al. 2002; McAndrews et al. 2005]. Cognitive impairment may be expressed in a wide variety of medical and psychiatric conditions, such as fatigue, depression, substance abuse among others. The detection of HCV genetic sequences in postmortem brain tissue raises the possibility that the presence of HCV in the central nervous system may explain the reported neuropsychological symptoms and cognitive impairment [Laskus et al. 2005].

Health-related quality of life (HRQoL) of patients with HCV, before antiviral treatment, is diminished compared with controls [Bonkovsky et al. 2007; Bonkovsky and Woolley, 1999; Kang et al. 2005]. HRQoL worsens with more advanced liver disease and therapy, leading to a reduction in adherence [Marcellin et al. 2011; Snow et al. 2010]. Based on the Short Form 36 Health Survey questionnaire, patients with HCV infection consistently show deficits in several domains, particularly those involving their physical role, general health and vitality versus healthy controls [McHutchison et al. 2001; Spiegel et al. 2005; Younossi et al. 2007]. HCV has been associated with a decreased ability to function both at work and at home, with obvious cost implications. Viral eradication correlates positively with improvements in HRQoL [Bonkovsky and Woolley, 1999; Cacoub et al. 2002]. Compared with placebo, a combination of sofosbuvir plus ribavirin was not associated with HRQoL impairment [Younossi Z et al. 2014]. Moreover, achieving SVR after 12 weeks of follow up with sofosbuvir and ribavirin was associated with improvement in HRQoL.

Depression has been documented in 28% of patients with HCV using the Structured Clinical Interview for DSM-IV Axis I Disorders [Golden et al. 2005]. HCV may directly affect the central nervous system through alterations in serotonergic and dopaminergic neurotransmission with resultant depressive symptoms [Cozzi et al. 2006]. This mechanism may explain other central nervous system symptoms seen in HCV infection, such as fatigue and cognitive impairment [Byrnes et al. 2012; Casato et al. 2005; Forton, 2006; Weissenborn et al. 2006]. Prior to starting antivirals including pegIFN, mental health should be assessed, as patients with a history of major depressive disorder are at greater risk of developing depression during HCV treatment. Antidepressant or antianxiolytic treatment may be considered before initiating IFN-based therapy.

Cognitive impairment is well described in chronic HCV infection. It is a common symptom in people with end-stage liver disease [Perry et al. 2008]. In the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial, 33% of 201 patients with advanced fibrosis who underwent neuropsychological testing had mild cognitive impairment on entering the trial [Fontana et al. 2005]. Patients with chronic HCV infection who are free from comorbid factors have higher levels of cognitive impairment than healthy controls [Lowry et al. 2010]. HCV eradication leads to improved cognitive function [Thein et al. 2007] and cerebral metabolism [Byrnes et al. 2012]. Patients with SVR demonstrated significant improvements in verbal learning, memory and visuospatial memory.

Fatigue is one of the most frequent and disabling complaints among patients with HCV (50–67%), and it independently predicts poor HRQoL [Kallman et al. 2007]. In a prospective study at the first visit of 1614 patients with HCV infection and in 412 healthy blood donors, fatigue was present in 53% of patients (51–56) versus 1% of controls (0–2) [Poynard et al. 2002]. Fatigue was independently associated with female sex, age over 50 years, cirrhosis and depression. Chronic fatigue is associated with bad sleep quality and increased nocturnal activity in patients with HCV, suggesting an alteration of sleep architecture in HCV-associated encephalopathy [Heeren et al. 2014].

Conclusion

Beyond the liver, HCV chronic infection leads to a multifaceted systemic disease. Some extrahepatic manifestations are immune mediated while others seem to be driven by chronic inflammation. Such extrahepatic manifestations should be well known by clinicians. They should have an impact on the care of patients with HCV infection. The need for effective eradication measures is underlined.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

References

Adinolfi, L., Restivo, L., Zampino, R., Guerrera, B., Lonardo, A., Ruggiero, L. et al. (2012) Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis 221: 496–502. doi:10.1016/j.atherosclerosis.2012.01.051.

Adinolfi

Zampino

Restivo

Lonardo

Guerrera

Marrone

(2014) Chronic hepatitis C virus infection and atherosclerosis: clinical impact and mechanisms. World J Gastroenterol 20: 3410–3417.

Aghemo

Prati

Rumi

Soffredini

D’Ambrosio

Orsi

(2012) Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C. Hepatology 56: 1681–1687.

Andreone

Zignego

Cursaro

Gramenzi

Gherlinzoni

Fiorino

(1998) Prevalence of monoclonal gammopathies in patients with hepatitis C virus infection. Ann Intern Med 129: 294–298.

Arcaini

Vallisa

Rattotti

Ferretti

Ferreri

Bernuzzi

(2014) Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi. Ann Oncol 25: 1404–1410.

Aslam

Alam

Lakkis

(2010) Hepatitis C and carotid atherosclerosis: a retrospective analysis. Atherosclerosis 209: 340–343.

Asrani

Buchanan

Pinsky

Rey

Schnitzler

Kanwal

(2010) Lack of association between hepatitis C infection and chronic kidney disease. Clin Gastroenterol Hepatol 8: 79–84.

Backus

Boothroyd

Phillips

Belperio

Halloran

Mole

(2011) A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 9: 509–516.e1.

Bonkovsky

Snow

Malet

Back-Madruga

Fontana

Sterling

. HALT-C Trial Group (2007) Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis. J Hepatol 46: 420–431.

10.

Bonkovsky

Woolley

(1999) Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group. Hepatology 29: 264–270.

11.

Boyer

Saadoun

Abriol

Dodille

Piette

Cacoub

(2004) CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 103: 3428–3430.

12.

Bronowicki

Loriot

Thiers

Grignon

Zignego

Bréchot

(1998) Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice. Hepatology 28: 211–218.

13.

Butt

Wang

Fried

(2011) HCV infection and the incidence of CKD. Am J Kidney Dis 57: 396–402.

14.

Butt

Xiaoqiang

Budoff

Leaf

Kuller

Justice

(2009) Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 49: 225–232.

15.

Byrnes

Miller

Lowry

Hill

Weinstein

Alsop

(2012) Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol 56: 549–556.

16.

Cacoub

Carrat

Bédossa

Lambert

Pénaranda

Pol

(2009) Insulin resistance impairs sustained virological response rate to pegylated interferon plus ribavirin in HIV-hepatitis C virus-coinfected patients: HOMAVIC-ANRS HC02 Study. Antivir Ther 14: 839–845.

17.

Cacoub

Poynard

Ghillani

Charlotte

Olivi

Piette

(1999) Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment virus C. Arthritis Rheum 42: 2204–2212.

18.

Cacoub

Ratziu

Myers

Ghillani

Piette

Moussalli

. Multivirc Group (2002) Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C. J Hepatol 36: 812–818.

19.

Cacoub

Renou

Kerr

Hüe

Rosenthal

Cohen

(2001) Influence of HLA-DR phenotype on the risk of hepatitis C virus-associated mixed cryoglobulinemia. Arthritis Rheum 44: 2118–2124.

20.

Cacoub

Renou

Rosenthal

Cohen

Loury

Loustaud-Ratti

(2000) Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d’Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l’Hepatite C. Medicine 79: 47–56.

21.

Caronia

Taylor

Pagliaro

Carr

Palazzo

Petrik

(1999) Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1059–1063.

22.

Casato

Saadoun

Marchetti

Limal

Picq

Pantano

(2005) Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests. J Rheumatol 32: 484–488.

23.

Cozzi

Zignego

Carpendo

Biagiotti

Aldinucci

Monti

(2006) Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients. J Viral Hepat 13: 402–408.

24.

Dal Maso

Franceschi

(2006) Hepatitis C virus and risk of lymphoma and other lymphoid neoplasms: a meta-analysis of epidemiologic studies. Cancer Epidemiol 15: 2078–2085.

25.

Dalrymple

Koepsell

Sampson

Louie

Dominitz

Young

(2007) Hepatitis C virus infection and the prevalence of renal insufficiency. Clin J Am Soc Nephrol 2: 715–721.

26.

Dammacco

Tucci

Lauletta

Gatti

De Re

Conteduca

(2010) Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study. Blood 116: 343–353.

27.

De Sanjose

Benavente

Vajdic

Engels

Morton

Bracci

(2008) Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol 6: 451–458.

28.

De Vita

Quartuccio

Fabris

(2008) Hepatitis C virus infection, mixed cryoglobulinemia and BLyS upregulation: targeting the infectious trigger, the autoimmune response, or both? Autoimmun Rev 8: 95–99.

29.

De Vita

Quartuccio

Isola

Mazzaro

Scaini

Lenzi

(2012) A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 64: 843–853.

30.

El-Kamary

Jhaveri

Shardell

(2011) All-cause, liver-related, and non-liver-related mortality among HCV-infected individuals in the general US population. Clin Infect Dis 53: 150–157.

31.

El-Serag

Hampel

Yeh

Rabeneck

(2002) Extrahepatic manifestations of hepatitis C among United States male veterans. Hepatology 36: 1439–1445.

32.

European Association for Study of Liver (2014) EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol 60: 392–420.

33.

Fabrizi

Poordad

Martin

(2002) Hepatitis C infection and the patient with end-stage renal disease. Hepatology 36: 3–10.

34.

Farghaly

Metwalley

El-Hafeez

(2014) Hepatitis C virus infection in Egyptian children with type 1 diabetes mellitus: a single center study. Indian J Endocrinol Metab 18: 197–201.

35.

Fontana

Bieliauskas

Back-Madruga

Lindsay

Kronfol

Lok

. HALT-C Trial Group (2005) Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial. J Hepatol 43: 614–622.

36.

Forton

(2006) Altered monoaminergic transporter binding in hepatitis C related cerebral dysfunction: a neuroimmunologial condition? Gut 55: 1535–1537.

37.

Forton

Thomas

Murphy

Allsop

Foster

Main

(2002) Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 35: 433–439.

38.

Fukui

Kitagawa

Nakamura

Yoshikawa

(2003) Hepatitis C virus and atherosclerosis in patients with type 2 diabetes. JAMA 289: 1245–1246.

39.

Galli

Zehender

Monti

Ballaré

Saccardo

Piconi

(1995) Hepatitis C virus RNA in the bone marrow of patients with mixed cryoglobulinemia and in subjects with noncryoglobulinemic chronic hepatitis type C. J Infect Dis 171: 672–675.

40.

Giannelli

Moscarella

Giannini

Caini

Monti

Gragnani

(2003) Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation. Blood 102: 1196–1201.

41.

Giannini

Giannelli

Zignego

(2006) Association between mixed cryoglobulinemia, translocation (14;18), and persistence of occult HCV lymphoid infection after treatment. Hepatology 43: 1166–1167.

42.

Giannini

Petrarca

Monti

Arena

Caini

Solazzo

(2008) Association between persistent lymphatic infection by hepatitis C virus after antiviral treatment and mixed cryoglobulinemia. Blood 111: 2943–2945.

43.

Gisbert

García-Buey

Pajares

Moreno-Otero

(2003) Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology 125: 1723–1732.

44.

Golden

O’Dwyer

Conroy

(2005) Depression and anxiety in patients with hepatitis C: prevalence, detection rates and risk factors. Gen Hosp Psychiatry 27: 431–438.

45.

Gragnani

Fabbrizzi

Triboli

Urraro

Boldrini

Fognani

(2014) Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: a prospective, controlled pilot study. Dig Liver Dis Off 46: 833–837.

46.

Hainsworth

Litchy

Burris

Scullin

Corso

Yardley

(2002) Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncol 20: 4261–4267.

47.

Heeren

Sojref

Schuppner

Worthmann

Pflugrad

Tryc

(2014) Active at night, sleepy all day–sleep disturbances in patients with hepatitis C virus infection. J Hepatol 60: 732–740.

48.

Hermine

Lefrère

Bronowicki

Mariette

Jondeau

Eclache-Saudreau

(2002) Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347: 89–94.

49.

Hsu

Kao

Chao

Lin

Fan

Huang

(2013) Interferon-based therapy reduces risk of stroke in chronic hepatitis C patients: a population-based cohort study in Taiwan. Aliment Pharmacol Ther 38: 415–423.

50.

Hsu

Lin

Kao

Huang

Hsiao

(2014) Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology 59: 1293–1302.

51.

Huang

Chuang

Dai

Hwang

Chen

(2006) Viral hepatitis and proteinuria in an area endemic for hepatitis B and C infections: another chain of link? J Intern Med 260: 255–262.

52.

Kallman

O’Neil

Larive

Boparai

Calabrese

Younossi

(2007) Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection. Dig Dis Sci 52: 2531–2539.

53.

Kang

Hwang

Lee

Chang

Lee

(2005) Health-related quality of life and impact of antiviral treatment in Chinese patients with chronic hepatitis C in Taiwan. World J Gastroenterol 11: 7494–7498.

54.

Kasama

Sekiguchi

Saito

Tanaka

Satoh

Kuwahara

(2010) Persistent expression of the full genome of hepatitis C virus in B cells induces spontaneous development of B-cell lymphomas in vivo. Blood 116: 4926–4933.

55.

Kawamura

Ikeda

Arase

Yatsuji

Sezaki

Hosaka

(2007) Viral elimination reduces incidence of malignant lymphoma in patients with hepatitis C. Am J Med 120: 1034–1041.

56.

KDIGO (Kidney Disease: Improving Global Outcomes) (2008) KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl S1–S99.

57.

Kelaidi

Rollot

Park

Tulliez

Christoforov

Calmus

(2004) Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia 18: 1711–1716.

58.

Koike

Moriya

Ishibashi

Yotsuyanagi

Shintani

Fujie

(1997) Sialadenitis histologically resembling Sjogren syndrome in mice transgenic for hepatitis C virus envelope genes. Proc Natl Acad Sci U S A 94: 233–236.

59.

Lai

Weiss

(1998) Hepatitis C virus and non-Hodgkin’s lymphoma. Am J Clin Pathol 109: 508–510.

60.

La Mura

De Renzo

Perna

D’Agostino

Masarone

Romano

(2008) Antiviral therapy after complete response to chemotherapy could be efficacious in HCV-positive non-Hodgkin’s lymphoma. J Hepatol 49: 557–563.

61.

Landau

Rosenzwajg

Saadoun

Klatzmann

Cacoub

(2009) The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders. Ann Rheum Dis 68: 337–344.

62.

Landau

Saadoun

Halfon

Martinot-Peignoux

Marcellin

Fois

(2008) Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis Rheum 58: 604–611.

63.

Laskus

Radkowski

Adair

Wilkinson

Scheck

Rakela

(2005) Emerging evidence of hepatitis C virus neuroinvasion. AIDS Lond Engl 19(Suppl. 3): S140–S144.

64.

Lee

Lin

Yang

Chen

Hwang

(2010) Association of hepatitis C and B virus infection with CKD in an endemic area in Taiwan: a cross-sectional study. Am J Kidney Dis 56: 23–31.

65.

Lee

Yang

Jen

You

Wang

. R.E.V.E.A.L.-HCV Study Group (2012) Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 206: 469–477.

66.

Lee

Yeon

Byun

Lee

Song

(1998) Cryoglobulinaemia and rheumatic manifestations in patients with hepatitis C virus infection. Ann Rheum Dis 57: 728–731.

67.

Liangpunsakul

Chalasani

(2005) Relationship between hepatitis C and microalbuminuria: results from the NHANES III. Kidney Int 67: 285–290.

68.

Libra

Indelicato

De Re

Zignego

Chiocchetti

Malaponte

(2005) Elevated serum levels of osteopontin in HCV-associated lymphoproliferative disorders. Cancer Biol Ther 4: 1192–1194.

69.

Libra

Mangano

Anzaldi

Quattrocchi

Donia

di Marco

(2006) Analysis of interleukin (IL)-1beta IL-1 receptor antagonist, soluble IL-1 receptor type II and IL-1 accessory protein in HCV-associated lymphoproliferative disorders. Oncol Rep 15: 1305–1308.

70.

Lowry

Coughlan

McCarthy

Crowe

(2010) Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients. J Viral Hepat 17: 352–359.

71.

Maasoumy

Wedemeyer

(2012) Natural history of acute and chronic hepatitis C. Best Pract Res Clin Gastroenterol 26: 401–412.

72.

Marcellin

Chousterman

Fontanges

Ouzan

Rotily

Varastet

. CheObs Study Group (2011) Adherence to treatment and quality of life during hepatitis C therapy: a prospective, real-life, observational study. Liver Int 31: 516–524.

73.

Maruyama

Koda

Oyake

Sato

Fujii

Horie

(2013) Myocardial injury in patients with chronic hepatitis C infection. J Hepatol 58: 11–15.

74.

Mason

Lau

Hoang

Qian

Alexander

(1999) Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 29: 328–333.

75.

Matsuo

Kusano

Sugumar

Nakamura

Tajima

Mueller

(2004) Effect of hepatitis C virus infection on the risk of non-Hodgkin’s lymphoma: a meta-analysis of epidemiological studies. Cancer Sci 95: 745–752.

76.

Mazzaro

De Re

Spina

Dal Maso

Festini

Comar

(2009) Pegylated-interferon plus ribavirin for HCV-positive indolent non-Hodgkin lymphomas. Br J Haematol 145: 255–257.

77.

McAndrews

Farcnik

Carlen

Damyanovich

Mrkonjic

Jones

(2005) Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 41: 801–808.

78.

McHutchison

Ware

Bayliss

Pianko

Albrecht

Cort

. Hepatitis Interventional Therapy Group (2001) The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity. J Hepatol 34: 140–147.

79.

Musto

Dell’Olio

Carotenuto

Mangia

Andriulli

(1996) Hepatitis C virus infection: a new bridge between hematologists and gastroenterologists? Blood 88: 752–754.

80.

Negri

Little

Boiocchi

La Vecchia

Franceschi

(2004) B-cell non-Hodgkin’s lymphoma and hepatitis C virus infection: a systematic review. Int J Cancer 111: 1–8.

81.

Omland

Jepsen

Krarup

Schønning

Lind

Kromann-Andersen

. DANVIR Cohort Study (2011) Increased mortality among persons infected with hepatitis C virus. Clin Gastroenterol Hepatol 9: 71–78.

82.

Perry

Hilsabeck

Hassanein

(2008) Cognitive dysfunction in chronic hepatitis C: a review. Dig Dis Sci 53: 307–321.

83.

Petta

Torres

Fazio

Cammà

Cabibi

Di Marco

(2012) Carotid atherosclerosis and chronic hepatitis C: a prospective study of risk associations. Hepatology 55: 1317–1323.

84.

Poynard

Cacoub

Ratziu

Myers

Dezailles

Mercadier

. Multivirc Group (2002) Fatigue in patients with chronic hepatitis C. J Viral Hepat 9: 295–303.

85.

Ramos-Casals

García-Carrasco

Cervera

Rosas

Trejo

de la Red

(2001) Hepatitis C virus infection mimicking primary Sjögren syndrome. A clinical and immunologic description of 35 cases. Medicine 80: 1–8.

86.

Ramos-Casals

Robles

Brito-Zerón

Nardi

Nicolás

Forns

(2006) Life-threatening cryoglobulinemia: clinical and immunological characterization of 29 cases. Semin Arthritis Rheum 36: 189–196.

87.

Retamozo, S., Díaz-Lagares, C., Bosch, X., Bové, A., Brito-Zerón, P., Gómez, M. et al. (2013) Life-threatening cryoglobulinemic patients with hepatitis C: clinical description and outcome of 279 patients. Medicine 22 August (epub ahead of print).

88.

Saadoun

Bieche

Authier

Laurendeau

Jambou

Piette

(2007) Role of matrix metalloproteinases, proinflammatory cytokines, and oxidative stress-derived molecules in hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy. Arthritis Rheum 56: 1315–1324.

89.

Saadoun

Bieche

Maisonobe

Asselah

Laurendeau

Piette

(2005a) Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy. Arthritis Rheum 52: 2917–2925.

90.

Saadoun

Delluc

Piette

Cacoub

(2008) Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol 20: 23–28.

91.

Saadoun

Pineton de Chambrun

Hermine

Karras

Choquet

Jego

(2013) Using rituximab plus fludarabine and cyclophosphamide as a treatment for refractory mixed cryoglobulinemia associated with lymphoma. Arthritis Care Res 65: 643–647.

92.

Saadoun

Resche Rigon

Sene

Terrier

Karras

Perard

(2010) Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood 116: 326–334; quiz 504–505.

93.

Saadoun

Resche-Rigon

Thibault

Piette

Cacoub

(2006) Antiviral therapy for hepatitis C virus–associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum 54: 3696–3706.

94.

Saadoun

Rosenzwajg

Joly

Six

Carrat

Thibault

(2011) Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365: 2067–2077.

95.

Saadoun

Suarez

Lefrere

Valensi

Mariette

Aouba

(2005b) Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood 105: 74–76.

96.

Sansonno

De Vita

Iacobelli

Cornacchiulo

Boiocchi

Dammacco

(1998) Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol 160: 3594–3601.

97.

Sansonno

Tucci

Ghebrehiwet

Lauletta

Peerschke

Conteduca

(2009) Role of the receptor for the globular domain of C1q protein in the pathogenesis of hepatitis C virus-related cryoglobulin vascular damage. J Immunol 183: 6013–6020.

98.

Sène

Ghillani-Dalbin

Thibault

Guis

Musset

Duhaut

(2004) Longterm course of mixed cryoglobulinemia in patients infected with hepatitis C virus. J Rheumatol 31: 2199–2206.

99.

Sène

Limal

Ghillani-Dalbin

Saadoun

Piette

Cacoub

(2007) Hepatitis C virus-associated B-cell proliferation – the role of serum B lymphocyte stimulator (BLyS/BAFF). Rheumatology 46: 65–69.

100.

Serfaty

Capeau

(2009) Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver Int 29(Suppl.2): 13–25.

101.

Snow

Bonkovsky

Fontana

Kim

Sterling

Di Bisceglie

. HALT-C Trial Group (2010) Changes in quality of life and sexual health are associated with low-dose peginterferon therapy and disease progression in patients with chronic hepatitis C. Aliment Pharmacol Ther 31: 719–734.

102.

Sosner

Wangermez

Chagneau-Derrode

Le Moal

Silvain

(2012) Atherosclerosis risk in HIV-infected patients: the influence of hepatitis C virus co-infection. Atherosclerosis 222: 274–277.

103.

Spiegel

Younossi

Hays

Revicki

Robbins

Kanwal

(2005) Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 41: 790–800.

104.

Sung

Shimodaira

Doughty

Picchio

Can

Yen

(2003) Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection. J Virol 77: 2134–2146.

105.

Taskoparan

Serin

Gokturk

Icer

Abaci

Ozer

(2011) Early effect of peginterferon alpha-2b plus ribavirin treatment on blood pressure and insulin resistance in patients with chronic hepatitis C. Hepatogastroenterology 58: 875–879.

106.

Terrier

Cacoub

(2013) Renal involvement in HCV-related vasculitis. Clin Res Hepatol Gastroenterol 37: 334–339.

107.

Terrier

Karras

Cluzel

Collet

Sène

Saadoun

(2013) Presentation and prognosis of cardiac involvement in hepatitis C virus-related vasculitis. Am J Cardiol 111: 265–272.

108.

Thein

Maruff

Krahn

Kaldor

Koorey

Brew

(2007) Improved cognitive function as a consequence of hepatitis C virus treatment. HIV Med 8: 520–528.

109.

Tsui

Vittinghoff

Shlipak

O’Hare

(2006) Relationship between hepatitis C and chronic kidney disease: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 17: 1168–1174.

110.

Tsukiyama-Kohara

Sekiguchi

Kasama

Salem

Machida

Kohara

(2011) Hepatitis C virus-related lymphomagenesis in a mouse model. ISRN Hematol 2011: 167501.

111.

Uto

Stuver

Hayashi

Kumagai

Sasaki

Kanmura

(2009) Increased rate of death related to presence of viremia among hepatitis C virus antibody-positive subjects in a community-based cohort study. Hepatology 50: 393–399.

112.

Vallat

Benhamou

Gutierrez

Ghillani

Hercher

Thibault

(2004) Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. Arthritis Rheum 50: 3668–3678.

113.

Vallisa

Bernuzzi

Arcaini

Sacchi

Callea

Marasca

(2005) Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin’s lymphoma: a multicenter Italian experience. J Clin Oncol 23: 468–473.

114.

Weissenborn

Ennen

Bokemeyer

Ahl

Wurster

Tillmann

(2006) Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut 55: 1624–1630.

115.

Wyatt

Malvestutto

Coca

Klotman

Parikh

(2008) The impact of hepatitis C virus coinfection on HIV-related kidney disease: a systematic review and meta-analysis. AIDS 22: 1799–1807.

116.

Younossi

Kallman

Kincaid

(2007) The effects of HCV infection and management on health-related quality of life. Hepatology 45: 806–816.

117.

Zignego

Bréchot

(1999) Extrahepatic manifestations of HCV infection: facts and controversies. J Hepatol 31: 369–376.

118.

Zignego

Ferri

Giannelli

Giannini

Caini

Monti

(2002) Prevalence of bcl-2 rearrangement in patients with hepatitis C virus-related mixed cryoglobulinemia with or without B-cell lymphomas. Ann Intern Med 137: 571–580.

119.

Zignego

Ferri

Pileri

Caini

Bianchi

Italian Association of the Study of Liver Commission on Extrahepatic Manifestations of HCV Infection . Extrahepatic manifestations of hepatitis C virus infection: a general overview and guidelines for a clinical approach. Dig Liver Dis. 200739: 2–17.

120.

Zignego

Giannelli

Marrocchi

Giannini

Gentilini

Innocenti

(1997) Frequency of bcl-2 rearrangement in patients with mixed cryoglobulinemia and HCV-positive liver diseases. Clin Exp Rheumatol 15: 711–712.

121.

Zignego

Giannelli

Marrocchi

Mazzocca

Ferri

Giannini

(2000) T(14;18) translocation in chronic hepatitis C virus infection. Hepatology 31: 474–479.

122.

Zignego

Giannini

Gragnani

(2012) HCV and lymphoproliferation. Clin Dev Immunol 2012: 980942.

123.

Zignego

Macchia

Monti

Thiers

Mazzetti

Foschi

(1992) Infection of peripheral mononuclear blood cells by hepatitis C virus. J Hepatol 15: 382–386.

124.

Zignego

Wojcik

Cacoub

Visentini

Casato

Mangia

(2014) Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. Genes Immun 15: 500–505.

Extrahepatic manifestations of chronic hepatitis C virus infection

Abstract

Keywords

Cryoglobulinemia vasculitis

B-cell lymphoproliferative diseases

Arthralgia/myalgia

Sicca syndrome

Autoantibodies

Cardiovascular diseases

Renal insufficiency

Insulin resistance and type 2 diabetes

Fatigue, depression and cognitive impairment

Conclusion

Footnotes

Funding

Conflict of interest statement

References