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. Introduction 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. Main extrahepatic manifestations in patients with hepatitis C virus infection. 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. Source
