A clinical textbook

Hepatology 2018

15. Extrahepatic manifestations of chronic HCV

Albrecht Böhlig, Karl-Philipp Puchner and Thomas Berg

Introduction

Patients with chronic hepatitis C virus (HCV) infection are at risk of a variety of extrahepatic manifestations (EHMs) (Table 1). It is estimated that about 90% of patients with chronic HCV infection will develop one or more EHMs during the course of the disease (Tang 2016, Negro 2015). EHMs may often be the first and only clinical sign of chronic hepatitis C infection. Evidence of HCV infection should always be ruled out in cases of non-specific chronic fatigue and/or rheumatic, hematological, endocrine or dermatological disorders. The pathogenesis of EHM is still not fully understood although most studies suggest that the presence of mixed cryoglobulinaemia, particularly HCV lymphotropism, molecular mimicry and non-cryoglobulinemic autoimmune phenomena constitute the major pathogenic factors (Ferri 2007). Nevertheless, the pathogenesis and epidemiology of many EHMs require further investigation (Figure 1). Our aim is to give a brief insight into the epidemiology, pathogenesis, clinical relevance and therapeutic management of HCV-associated EHM (Zignego 2007a).

Mixed cryoglobulinaemia

Cryoglobulinaemia refers to the presence of abnormal immunoglobulins in the serum, which have the unusual property of precipitating at temperatures below 37°C and redissolving at higher temperatures. The phenomenon of cryoprecipitation was first described in 1933 (Wintrobe 1933). Cryoglobulins (CGs) are nowadays classified into three types (Table 2) based on their clonality. Type II CG and type III CG, consisting of monoclonal and/or polyclonal immunoglobulins, are prevalent in patients with chronic HCV infection, while type I CGs, consisting exclusively of monoclonal components, are mostly found in patients with lymphoproliferative disorders (multiple myeloma, B cell lymphoma, Waldenström macroglobulinaemia). Type II or type III mixed cryoglobulinaemia is found in 19%-50% of patients with chronic HCV but leads to clinical manifestations through vascular precipitation of immunocomplexes in only 30% of them (Lunel 1994, Wong 1996). Asymptomatic mixed cryoglobulinaemia (MC) during the course of chronic HCV infection may evolve into symptomatic disease. Patients with symptomatic mixed cryoglobulinaemia (MCS) exhibit higher cryoglobulin concentrations (cryocrit >3%) and lower concentrations of complement factors C3 and C4 (Weiner 1998). Thus CG-triggered complement activation may constitute a key incidence in cryoglobulinaemia-derived pathogenesis. Factors that seem to favour the development of MC are female sex, age, alcohol intake (>50g/d), advanced liver fibrosis and steatosis (Lunel 1994, Wong 1996, Saadoun 2006).

Table 1. Extrahepatic manifestations of chronic hepatitis C infection
Organ/System involved Manifestation
Endocrine disorders
  • Autoimmune thyroidopathies (in particular, Hashimoto thyroiditis)
  • Insulin resistance/diabetes mellitus*
  • Growth hormone (GH) insufficiency
  • Vitamin D deficiency
  • Ostepenia and Osteoporosis
Rheumatic disorders
  • Mixed cryoglobulinaemia*
  • Cryoglobulinemic vasculitis*
  • Peripheral neuropathy*
  • Membrano-proliferative glomerulonephritis (GN)*
  • Membranous GN*
  • Rheumatoid arthralgias/oligopolyarthritis
  • Rheumatoid factor positivity*
  • Sicca syndrome
Hematologic disorders
  • Lymphoproliferative disorders/Non-Hodgkin Lymphomas*
  • Immune thrombocytopenic purpura (ITP)
  • Monoclonal gammopathies*
  • Autoimmune hemolytic anaemia
Dermatologic disorders
  • Palpable purpura
  • Porphyria cutanea tarda (PCT)
  • Lichen planus
  • Pruritus
Cardiovascular disorders
  • Cardiomyopathy/Myocarditis
  • Carotid atherosclerosis
  • Increased risk for peripheral arterial disease (PAD), cardiovascular (CV) mortality, and ischemic stroke
Central nervous system disorders
  • Chronic fatigue*, subclinical cognitive impairment, psychomotoric deceleration, symptoms of depression*
  • Neurocognitive disorders
Miscellaneous
  • Myopathy
  • Idiopathic pulmonary fibrosis
  • Increased risk for non-liver solid cancers (rectum, pancreas, lung and bronchus, kidney) (Allison 2015)
*Associations based on strong epidemiological prevalence and/or clear pathogenetic mechanisms Table 2. Types of cryoglobulinaemia
Type Clonality
Type I Monoclonal immunoglobulins (IgG or IgM)
Type II Polyclonal immunoglobulins (mainly IgG) and monoclonal IgM with rheumatoid factor activity (RF)
Type III Polyclonal IgG and IgM
Figure 1. Schematic representation of EHM categories according to the strength of association (Ferri 2016). 1: Strong association with HCV as main etiological agent, 2: Association demonstrated in a significant proportion of patients compared to the general population. 3: Suggested role of HCV infection demonstrated in cohort studies. 4: Anecdotal observations suggested a possible role of HCV. PCT: porphyria cutanea tarda, PAN: periarteriitis nodosa, IBM: inclusion body myositis, SLE: systemic lupus erythematodes, PM/DM: polymyositis/dermatomyositis, APS: anti-phospholipid syndrome.

Diagnosis

Detection of CG is carried out by keeping patient serum at 4°C for up to 7 days. When cryoprecipitate is visible, CG can be purified and characterised using immunofixation electrophoresis. In case of evidence of mixed cryoglobulinaemia in HCV positive patients, cryoglobulinemic syndrome needs to be looked for. Vigilant monitoring is required, as asymptomatic mixed cryoglobulinaemia patients may develop MC-related disorders in the course of the disease. The diagnosis of the MC syndrome is based on serologic, pathologic and clinical criteria (Table 3).

Table 3. Diagnostic criteria of cryoglobulinemic syndrome
Serologic Histopathologic Clinical
  • C4 reduction
  • Positive rheumatoid factor (RF)
  • CGs, type II or III
  • HCV antibodies
  • Leucocytoclastic vasculitis
  • Monoclonal B-cell infiltrates
  • Purpura
  • Fatigue
  • Arthralgia
  • Membranoproliferative GN
  • Peripheral neuropathy

In the presence of mixed CG, low C4 counts, leucocytoclastic vasculitis and purpura, a definite symptomatic MC can be diagnosed. Rheumatoid factor (RF) determination constitutes a reliable surrogate marker for detection of CG. Finally, presence of CG may impair HCV RNA determination as viral RNA can accumulate in precipitated cryocrit (Colantoni 1997).

Clinical presentation

HCV-related MC proceeds mostly asymptomatically and has no significant influence on the course of chronic liver inflammation. On the other hand, symptomatic mixed cryoglobulinaemia is associated with higher mortality (Ferri 2004).

Systemic vasculitis

HCV-related vasculitis relies on a deposition of immunocomplexes containing CGs, complement and large amounts of HCV antigens in the small- and medium-sized blood vessels. HCV accumulates in the CG immunoglobulins. Pathohistological findings reveal a leucocytoclastic vasculitis (Agnello 1997). The most common symptoms of mixed cryoglobulinemic vasculitis are weakness, arthralgia and purpura (the Meltzer and Franklin triad). Mixed cryoglobulinemic vasculitis may also lead to Raynaud’s Syndrome and Sicca Syndrome, glomerulonephritis and peripheral neuropathy.

Renal impairment

The predominant renal impairment associated with mixed cryoglobulinaemia is the membranous proliferative glomerulonephritis (MPGN), characterised in most cases by proteinuria, mild hematuria and mild renal insufficiency. The presence of kidney impairment is considered to be a negative prognostic factor in the course of the disease (Ferri 2004). In 15% of patients, MC-related nephropathy may progress to terminal chronic renal failure requiring dialysis (Tarantino 1995).

Peripheral neuropathy

Peripheral neuropathy, on the basis of endoneural microangiopathy, constitutes a further typical complication of mixed cryoglobulinaemia. MC-related neuropathy, presenting clinically as mononeuropathy or polyneuropathy, is mostly sensory and is characterised by numbness, burning skin, a crawling sensation, and pruritus, predominantly in the hands and feet (Tembl 1999, Lidove 2001). Epidemiological data from Italy suggests that peripheral neuropathy is the second most common symptom after the Meltzer and Franklin triad in patients with symptomatic HCV-associated mixed cryoglobulinaemia (Ferri 2004).

Cirrhosis

The causal association between CG and progression of liver fibrosis suggested by numerous authors was not confirmed in a published 10-year prospective study. The 10-year rates of progression to cirrhosis were similar in cryoglobulinemic and non-cryoglobulinemic HCV-infected patients (Vigano 2007). From this, it is unlikely that mixed cryoglobulinaemia constitutes an independent risk factor for the progression of liver fibrosis.

Malignant lymphoproliferative disorders/NHL

The association between infectious agents and potentially reversible “antigen driven” lymphoproliferative disorders, such as Helicobacter pylori-related gastric marginal zone B cell lymphoma has been known for many decades. Recent data suggest a causative association between HCV and Non-Hodgkin Lymphoma (NHL) (Mele 2003, Duberg 2005, Giordano 2007). HCV infection leads per se to a two-fold higher risk of developing NHL (Mele 2003, Duberg 2005). The most prevalent HCV-associated lymphoproliferative disorders according to the REAL/WHO classification are: follicular lymphoma, B cell chronic lymphocytic leukaemia/small lymphocyte lymphoma, diffuse large B cell lymphoma and marginal zone lymphoma, including the mucosa-associated lymphoid tissue lymphoma. Overall, marginal zone lymphoma appears to be the most frequently encountered low grade B cell lymphoma in HCV patients. The role of HCV in the genesis of lymphoma can be either explained by the direct lymphoma-inducing effects of HCV during viral replication in normal B cells or by being a stochastic process as a result of HCV-induced proliferation of B cells (Agnello 2004, Figure 2). More recent data from a large population-based study comparing HCV-infected patients with the general population showed a more than doubled age-adjusted mortality rate for NHL among HCV-infected patients. In addition, there was a trend towards higher grades and stages of NHL in the HCV group compared to the control population (Allison 2015).

HCV-associated lymphoproliferative disorders (LPDs) are observed over the course of MC. 8-10% of mixed cryoglobulinaemia type II evolve into B cell NHL after long-lasting infection. However, a remarkably high prevalence of B cell NHL was also found in HCV patients without mixed cryoglobulinaemia (Silvestri 1997). Genetic predisposition and other factors seem to have a major impact on the development of LPDs in HCV positive patients (Matsuo 2004).

Aetiology and pathogenesis of LPDs in patients with HCV infection

In the development of LPDs direct and indirect pathogenic HCV-associated factors (Figure 2) are seen. Sustained B cell activation and proliferation, noticed during chronic HCV infection, is an indirect pathogenic mechanism.

Direct pathogenic mechanisms are based on lymphotropic properties of HCV, hence on HCV’s entry into the B cells. HCV RNA sequences were first detected in mononuclear peripheral blood cells (Zignego 1992). Especially CD19+ cells seem to be permissive for certain HCV quasispecies (Roque Afonso 1999). Active replication of the HCV genome in B cells is associated with activation of anti-apoptotic gene BCL-2 and inhibition of p53 or c-Myc-induced apoptosis (Sakamuro 1995, Ray 1996). In this light, direct involvement of HCV in the immortalisation of B cells can be imagined (Zignego 2000, Machida 2004).

More recent data show that the lymphotropism of HCV with its association to B cells is mediated by the complement system involving the complement receptor 2 (CD21) and CD19 as well as CD81 complex (Wang 2016). A complex dysregulated cytokine network involving Th1 immune response and proinflammatory cytokines has been shown to be present in HCV-EHMs. IFN γ as well as CXCL9, CXCL10 and CXCL11 chemokines are responsible mediators of liver inflammation and parenchyma damage during the course of the infection. CXCL10 levels have been shown to decrease after successful DAA therapy of HCV infection (Fallahi 2017).

Figure 2. Aetiology and pathomechanisms involved in chronic HCV infection and the development of malignant lymphoproliferative disorders. Multiple pathogenetic processes are involved such as chronic HCV infection, environmental triggers or genetic predisposition. HCV-induced lymphoproliferation and autoantibody production can be distinguished from oncogenic alterations leading to B cell neoplasias and other malignancies (B-NHL, HCC, papillary thyroid cancer). Significant molecularpathogenetic steps are binding of HCV protein E2 to CD81 following t(14;18) translocation as well as proto-oncogen bcl-2 activation, cross reaction between HCV antigens and host autoantigens and direct B cell infection by HCV followed by neoplastic transformation. HCV-induced B cell proliferation with production of various autoantibodies may be the pathological substrate of organ- and non-organ-specific autoimmune disorders, such as MC syndrome or cryoglobulinemic vasculitis (RF: rheumatoid factor, NHL: non-Hodgkin’s lymphoma, HCC: hepatocellular carcinoma, PCT: porphyria cutanea tarda, modified after Ferri C et al., 2017).

Treatment of lymphoproliferative disorders

Because of the close correlation between the level of viral suppression and improvement of HCV-associated extrahepatic symptoms, the most effective antiviral strategy should be considered when dealing with HCV-related extrahepatic diseases. New interferon-free combinations of direct acting antiviral drugs (DAA) are the standard of care for HCV infection types 1-6. Therefore these regimens can also be regarded as treatment of choice in HCV-infected patients with extrahepatic manifestations. However, the clinical experience of DAA use in patients with EHM remains limited because only less than 100 of such cases were reported in the last two years. Compared to interferon-based therapies the newer DAAs have a very small number of true contraindications. However drug-drug interactions due to CYP3A or P-glycoprotein metabolism need to be taken into account and concomitant medications need to be assessed and adjusted accordingly. For further information, see the other HCV chapters.

Mixed cryoglobulinaemia

While asymptomatic mixed cryoglobulinaemia (MC) per se does not constitute an indication for treatment, symptomatic mixed cryoglobulinaemia (MCS) should always be treated. Because asymptomatic cryoglobulinaemia may evolve into symptomatic CG in the course of disease, vigilant monitoring is required and introduction of antiviral therapy in terms of prophylaxis should be considered.

Because a causal correlation between HCV infection and mixed cryoglobulinaemia has been established, the therapeutic approach of symptomatic mixed cryoglobulinaemia should primarily concentrate on the eradication of the virus. In the therapeutic era of interferon, IFN α has been shown to be a promising therapeutic tool in HCV-induced MC due to its antiviral, and antiproliferative properties on IgM-RF-producing B cells and stimulation of macrophage-mediated clearance of immunocomplexes, suggesting that IFN α may lead to clinical amelioration even in virologic non-responders. Clinical improvement of MC is reported in 50 to 70% of patients receiving antiviral therapy with IFN α plus RBV and mostly correlates with a significant reduction of HCV RNA concentrations (Calleja 1999). However, cryoglobulinemic vasculitis following successful antiviral treatment persists in a small collective (Levine 2005). Data from a large prospective study in chronically HCV-infected patients with MC who have been treated with Peg-IFN α plus ribavirin confirmed the close relationship between virologic response and clinical-immunological response. Indeed, all patients with sustained virologic response also experienced a sustained clinical response, either complete or partial. In the majority of sustained virologic response patients all MCS symptoms persistently disappeared (36 patients, 57%); in only two (3%) did definite MCS persist. All virologic non-responders were also clinical non-responders, in spite of a transient improvement in some cases (Gragnani 2015). In case of treatment failure of antiviral therapy and/or fulminant manifestations, contraindications or severe side effects, alternative therapeutic strategies such as cytostatic immunosuppressive therapy and/or plasmapheresis have been considered in the interferon era (Craxi 2008) (Figure 3, Table 4). Recent data show rituximab as an effective and safe treatment option for MC even in advanced liver disease. Moreover, B cell depletion has been shown to improve cirrhotic syndrome by mechanisms that remain to be elucidated (Petrarca 2010).

In the treatment era of IFN-free DAA regimens, eleven studies with 120 patients have reported on the use of DAA regimens in HCV-induced EHMs since 2015. Most out of these had cyroglobulinemic vasculitis (Ramos-Casals 2017; see also Table 4). There is first data revealing a successful treatment of a genotype 3 HCV patient with decompensated cirrhosis and renal failure secondary to MCS. 12 week-treatment with sofosbuvir, ledipasvir and ribavirin led to SVR and improvement of liver and renal function in this patient, yet further studies with larger cohorts are required to confirm these results (Flemming 2016).

Systemic vasculitis

In cases of severe systemic vasculitis, initial therapy with rituximab, a monoclonal chimeric antibody against CD20 B cell-specific antigen, is suggested. Its efficacy and safety have been demonstrated in patients with symptomatic MC resistant to IFN α therapy, even though HCV RNA increased approximately twice the baseline levels in responders (Sansonno 2003). In the interferon era, a combined application of rituximab with PEG-IFN α plus ribavirin was considered a rational approach for cases with severe mixed cryoglobulinaemia-related vasculitis resistant to antiviral therapy alone (Saadoun 2008). However, the future role of rituximab and other immunosuppressive regimens remain to be seen in the light of the new interferon-free antiviral treatment era, in which nearly all patients can be quite effectively treated and cured from their HCV infection. Still, clinical experience in treatment of EHMs with DAA therapy is rather limited. First evidence of the efficacy and safety of DAA based treatment with sofosbuvir-based regimens in patients with HCV-induced MC was recently published by Sise et al. demonstrating an SVR12 rate of 83%. Interestingly, treatment response was associated with an improvement in eGFR and a reduction in proteinuria (Sise 2015). In severe mixed cryoglobulinaemia-related vasculitis or acute manifestations refractory to both, antiviral and rituximab-based approaches, cycles of plasma exchange plus corticosteroids and eventually cyclophosphamide are indicated. Further studies showed that low dose interleukin-2 can lead to clinical improvement of vasculitis and has immunologic effects such as recovery of regulatory T cells (Saadoun 2011).

Regarding the IFN-free DAA regimens, there is a cohort of 24 HCV patients with CV who were treated with sofosbuvir+RBV, A clinical response was observed in most patients (87,5%) and 74% of patients achieved SVR24 (17/23) (Saadoun 2015b). Treatment with sofosbuvir+RBV (n=18) as well as combination of sofosbuvir+RBV plus simeprevir or ledipasvir or daclatasvir was analysed in a recent trial with 28 CV patients from whom 12 patients had cirrhosis. Here SVR24 was 100%, although there are no data on immunological response (Gragnani 2016). There are also some data on DAA regimens in patients with EHM without the use of RBV. In a retrospective study of 8 CV patients who were treated with sofosbuvir and simeprevir, there was an SVR12 rate of 87,5% (7/8). A complete clinical resonse for CV was only seen in half of the patients (4/8) (Sise 2016). More recently, data of n=30 and n=16 HCV patients with CV were published using many different DAA regimens for HCV treatment, including 3D, sofosbuvir, simeprevir, daclatasvir, grazoprevir and elbasvir. The CGs became negative in 12 of 30 patients and the SVR24 rates were constantly high (29/30 and 16/16 patients) (Bonacci 2016, Gragnani 2016). Taken together, an interferon-free DAA regimen represents the current standard of care for HCV-infected patients with EHM. For selecting the most appropriate DAA regimen certain host and viral factors but also co-medications have to be taken into considerations as outlined in current HCV treatment guidelines (Ramos-Casals 2017; EASL guideline 2018).

Peripheral neuropathy

Cryoglobulinaemia-induced peripheral neuropathy has been a significant issue in the past, because the effectiveness of interferon-based antiviral therapy on peripheral neuropathy has been debated intensely. While HCV-related peripheral neuropathy responsive to antiviral therapy with IFN α plus ribavirin in 4 patients with chronic HCV has been reported (Koskinas 2007), several authors report on an aggravation of cryoglobulinemic neuropathy or even de novo occurrence of demyelinating polyneuropathy during IFN α and PEG-IFN α treatment (Boonyapist 2002, Khiani 2008). Therefore, application of IFN α in the presence of HCV-related neuropathy requires a cautious risk-benefit assessment. First data on efficacy of DAA treatment on HCV-related neuropathy show promising results with total resolution of polyneuropathy in 21 of 25 patients under sofosbuvir-based regimens (Hegazy 2016). Therefore, peripheral neuropathy should not be any more considered as a contraindication for antiviral therapy of the chronic hepatitis C. However, another study found a small proportion of DAA-treated patients with presence of severe cryoglobulinemic vasculitis and peripheral neuropathy being associated with non-response to therapy (Cacoub 2018).

Figure 3. Therapeutic algorithm for symptomatic HCV-related mixed cryoglobulinaemia (Ramos-Casals 2012). Antiviral therapy, i.e., combination therapy with direct acting antivirals (+/- ribavirin), is regarded as first-line therapy in cases of mild/moderate manifestations. In case of contraindications, patients should be treated primarily with corticosteroids. Long-term therapy with corticosteroids may result in elevation of viral load and progression of hepatic disease. In light of this, rituximab represents an attractive alternative, because in this case, drug-induced viral load escalation is minor. In patients with severe manifestations, treatment should focus on both DAA therapy and immunosuppression (± plasmapheresis). Due to its excellent immunosuppressive properties and relatively mild side effect profile, use of rituximab should be favoured. Therapy-refractory cases require individual treatment according to the particular center’s experience.

As eradication of Helicobacter pylori may lead to complete remission of MALT lymphoma, antiviral therapy can lead to regression of low-grade NHL in patients with HCV-related malignant lymphoproliferative disorders. Combination therapy with direct acting antivirals (+/- ribavirin) should be regarded in such cases as first-line therapy (Giannelli 2003, Vallisa 2005). Remission of the hematologic disorders is closely associated with virologic response or rather achievement of sustained virologic response.

Table 4. Overview of selected studies evaluating different antiviral but also rituximab-based treatment strategies of cryoglobulinaemia-related disorders in patients with chronic HCV infection
Author Patients Treatment Result
Sansonno N=20
MC vasculitis and peripheral neuropathy resistant to IFN α montherapy
Rituximab 375 mg/m2/ 4x/wk 16 patients with complete clinical response; 12 sustained response throughout follow-up. Viraemia increases in responders
Saadoun N=16
MC vasculitis in relapsers or non-responders to IFN α/PEG-IFN α + RBV
Rituximab 375 mg/m2/ 4x/wk; PEG-IFN α 1.5 ug/kg/wk + RBV (600–1200 mg/d) for 12 months 10/16 report complete clinical response; CGs and HCV RNA undetectable in responders
Roccatello N=6
MC systematic manifestations predominantly renal (5/6)
Rituximab 375 mg/m2/4x/wk + rituximab 375 mg/m2 1 month and 2 months later Decrease of cryocrit and proteinuria at months 2, 6, 12
De Nicola N=1
Cyroglobulinemic membrano-proliferative GN
Telaprevir + PEG-IFN + RBV Complete resolution of acute renal failure from nephritic syndrome, undetectable HCV RNA
Saadoun N=30
MC vasculitis; 23/30 non-responders to previous antiviral treatment
Telaprevir (12 wks) + PEG-IFN α + RBV (48 wks) or boceprevir (44 wks) + PEG-IFN α + RBV (48 wks) CGs decreased from 0.45 to 0 g/L; clinical and sustained viral response in 20/30 (66.7%)
Sise N=12
HCV-related MC with systemic vasculitis; renal manifestation (N=7)
Sofosbuvir + ribavirin (12 or 24 wks) or sofosbuvir + simeprevir (12 wks) Overall SVR12 83%; 86% SVR12 in patients with kidney involvement (6/7); decrease of CG levels in 89%
Gragnani N=44
HCV-related MC with active cryoglobulinemic vasculitis
Sofosbuvir monotherapy or + simeprevir or + daclatasvir or + ledipasvir (+/- ribavirin) SVR12 and SVR24: 100%, MC response at SVR24: 36% full complete response, 41% complete response, 23% partial response
Bonacci N=30
MC vasculitis
Ombitasvir + paritraprevir + ritonavir + dasabuvir or Ledipasvir + sofosbuvir or simeprevir + daclatasvir or grazoprevir + elbasvir and other regimens SVR24: 97% (29/30); complete clinical response 22/30, CGs negative 12/30
Saadoun N=41
MC vasculitis
Sofosbuvir + daclatasvir (12 or 24 wks) SVR12: 100% (41/41); 90,2% complete clinical response (37/41); no CGs detectable at week 36 in 50%

Treatment of HCV-infected patients with high-grade NHL should be based on cytostatic chemotherapy according to current guidelines from hematologic societies. HCV infection does not constitute a contraindication for cytostatic chemotherapy. Unlike HBV infection, antiviral prophylaxis before chemotherapy introduction is not obligatory. Chemotherapy may lead to a substantial increase in viraemia. Consecutive exacerbation of the infection, making discontinuation of chemotherapy mandatory, is however unlikely to occur. However, treatment-related liver toxicity is more frequent in HCV positive NHL and is often associated with severe hepatic manifestations (Besson 2006, Arcaini 2009). Current data suggest that antiviral treatment may serve as maintenance therapy for achieving sustained remission of NHL after chemotherapy completion (Gianelli 2003).

Further hematological manifestations

HCV-associated thrombocytopenia

Thrombocytopenic conditions (platelet counts below 150 x 103/uL) are often observed in patients with chronic hepatitis C and result mainly from advanced liver fibrosis and manifest cirrhosis with portal hypertension and consecutive splenomegaly (Wang 2004). Lack of hepatic-derived thrombopoietin can inter alia be recognised as an important causal factor (Afdhal 2008). As HCV RNA can be abundant in platelets (Takehara 1994) and megakaryocytes of thrombocytopenic patients, direct cytopathic involvement of HCV can be hypothesised (Bordin 1995, De Almeida 2004). Furthermore, it has been suggested that exposure to HCV may be a causative factor for the production of platelet-associated immunoglobulins, inducing thrombocytopenia through a similar immunological mechanism to that operating in immune thrombocytopenic purpura (ITP) (Aref 2009). There is a high HCV prevalence in patients with ITP (García-Suaréz 2000), and these patients exhibit diverse characteristics to HCV negative patients with ITP, which supports the hypothesis of direct viral involvement in the development of thrombocytopenia (Rajan 2005).

There is no consensus regarding the optimum treatment of HCV-related ITP. Along with classical therapeutic approaches such as corticosteroids, intravenous immunoglobulins and splenectomy, antiviral therapy constitutes another option. A substantial increase of platelets after application of antiviral therapy is registered in a significant percentage of patients with HCV-related ITP (Iga 2005), although evidence from further studies is required to confirm this hypothesis. However, caution is recommended in thrombocytopenic patients treated with PEG-IFN α plus ribavirin, as significant aggravation of HCV-related ITP may occur on this regimen (Fattovich 1996). On the other hand, long-term use of steroids or immunosuppressive drugs is limited by an increased risk of fibrosis progression or a substantial elevation of virus, respectively.

An orally active thrombopoietin receptor agonist, eltrombopag, may be used in thrombocytopenic HCV patients. Its efficacy has been documented in patients with HCV-related ITP (Bussel 2007) as well as in HCV positive patients suffering from thrombocytopenia due to cirrhosis (McHutchison 2007), although, in a recent study treating patients with eltrombopag in combination with PEG-IFN α and ribavirin, portal vein thrombosis was observed in a number of patients as an unexpected complication (Afdhal 2011). FDA recently approved a new indication for eltrombopag for patients with thrombocytopenia with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. However, in countries with access to interferon-free regimens this indication may become obsolete as direct acting antivirals do not aggravate thrombocytopenia.

In case of refractory disease or aggravation during the course of antiviral therapy, rituximab should be considered (Weitz 2005).

HCV-related autoimmune hemolytic anaemia

Interpretation of autoimmune hemolytic anaemia (AHA) as a possible EHM is based mainly on a few well-documented case reports (Chao 2001, Fernandéz 2006, Srinivasan 2001). AHA has been frequently observed in HCV patients treated with IFN α with and without ribavirin and consequently recognised as a possible side effect of antiviral treatment (De la Serna-Higuera 1999, Nomura 2004). Recently, a large-scale epidemiological study confirmed a high incidence of AHA in HCV patients undergoing antiviral treatment. However, the incidence rate of AHA in treatment-naïve HCV patients was statistically insignificant (Chiao 2009). Therefore, for the time being, there is little evidence for regarding AHA as a possible EHM of chronic HCV infection.

HCV-related glomerulonephritis

Data from national cohort studies show that HCV-infected patients have a higher prevalence of chronic kidney disease (CKD) and especially diabetes, hyperlipidaemia and cirrhosis showed to increase the risk for CKD in HCV-infected individuals (Chen 2014). Moreover, presence of HCV has been shown to be associated with deterioration of kidney function. A recent large cohort study with over 100.000 HCV infected US veterans and over 900.000 non-HCV controls found an almost two-fold increased risk of developing end-stage renal disease in HCV-infected individuals compared to non-HCV-infected controls (Molnar 2015). Glomerulonephritis (GN) constitutes a rare extrahepatic complication of chronic HCV. Predominant manifestations are cryoglobulinemic or non-cryoglobulinemic membranous proliferative GN and mesangioproliferative GN. Far less common is membranous nephropathy (Arase 1998). Other forms of GN do not correlate significantly with HCV infection (Daghestani 1999). Microhematuria and proteinuria are among the most frequent medical findings in patients with membranous proliferative GN. Approximately 50% of patients exhibit a mild renal insufficiency. 20-25% may present an acute nephritic syndrome (hematuria, hypertension and proteinuria), as in 25% of patients nephrotic syndrome represents the initial manifestation. In contrast, >80% of patients with HCV-related membranous nephropathy suffer primarily a nephrotic syndrome (Doutrelepont 1993, Rollino 1991). The mesangioproliferative form proceeds mostly asymptomatically, with typical findings such as hematuria and proteinuria often missing (McGuire 2006).

The pathomechanism of renal impairment is yet not fully understood. It can be hypothesised that glomerular injury is primarily caused by a deposition of circulating immunocomplexes containing anti-HCV antibodies, HCV antigens and complement factors. Formation and deposition of such immunocomplexes occurs also in the absence of CGs. HCV proteins in glomerular and tubulointerstitial structures are immunohistologically detectable in approximately 70% of patients with chronic HCV (Sansonno 1997). Further possible pathomechanisms of glomerular injury encompass formation of glomerular autoantibodies, glomerular impairment due to chronic hepatic injury, or IgM overproduction with consecutive glomerular IgM deposition as a result of HCV-triggered cryoglobulinaemia type II. GN prevalence in HCV patients is estimated at 1.4% and is comparably high due to its prevalence among blood donors (Paydas 1996).

HCV-induced GN has mostly a benign prognosis (Daghestani 1999). 10-15% of patients with nephritic syndrome experience spontaneous complete or partial remission. Frequently persisting mild proteinuria exhibits no tendency to progression. It is estimated that only approximately 15% of the patients with HCV-related GN develop terminal renal failure requiring dialysis (Tarantino 1995). Nevertheless, presence of kidney impairment is considered to be a negative prognostic factor for long-term survival (Ferri 2004).

Patients with HCV-related GN should be primarily treated with direct acting antivirals. In cases of mild renal impairment, sustained viral response normally leads to amelioration of proteinuria or even full remission of GN. With high baseline viraemia and advanced renal insufficiency, antiviral therapy is subject to certain limitations (Sabry 2002). Despite amelioration of proteinuria achieved after antiviral therapy, significant improvement of renal function is often lacking (Alric 2004). Ribavirin dosage must be cautiously adjusted to glomerular filtration rate (GFR), in order to mainly prevent ribavirin accumulation with consecutive hemolytic anaemia (Fabrizi 2008). RBV-induced hemolytic anaemia was efficiently treated by administration of erythropoietin and erythrocyte concentrates (van Leusen 2008). As determination of RBV blood levels is not an established laboratory procedure, implementation of such a therapeutic approach in clinical routine remains arduous. Renal impairment was observed as an adverse event associated with the use of telaprevir and boceprevir (Mauss 2014). In patients with severe renal insufficiency (eGFR <30 ml/min), data for the use of simeprevir, ledipasvir, sofosbuvir and other direct acting antivirals are emerging. Although the use of sofosbuvir is currently not recommend in patients with eGFR <30 ml/min, safety and efficacy of full dose sofosbuvir regimen was recently shown in this population (Hundemer 2015). The 3 D regimen, comprising of paritaprevir/ritonavir/ombitasvir + dasabuvir as well as the NS5A inhibitor daclatasvir have been safely administered in patients with severe renal insufficiency (GFR <30 ml/min) due to the predominant biliary elimination of these drugs (Fabrizi 2015). The regimen of grazoprevir plus elbasvir has been evaluated in a large cohort of 235 HCV patients with serious renal involvement. These drugs have a renal elimination rate less than 1%. Therefore, the 3 D regimen as well as grazoprevir plus elbasvir are currently the only approved combination therapies in end-stage renal disease (GFR <15 ml/min) (Cacoub 2016). However, therapy with glecaprevir/pibrentasvir is also possible and should be favoured and, if available, replace the 3 D regimen. Currently, grazoprevir plus elbasvir is the recommended therapeutic regimen in HCV type 1 patients with severe or terminal renal insufficiency (AFEF 2016) (see also Chapters 13, 14).

Fulminant manifestations with impending acute renal failure can be treated with corticosteroids, cyclosporine, and other immunosuppressive drugs such as cyclophosphamide and eventually plasmapheresis (Garini 2007, Margin 1994). In case of simultaneous bone marrow B cell infiltration and/or resistance to conventional therapy, application of rituximab is indicated (Roccatello 2004). Rituximab may be used as an alternative first line therapy in severe renal manifestations (Roccatello 2008). Antiviral and immunosuppressive therapy should always be supplemented with ACE inhibitors or AT1 receptor antagonists (Kamar 2006).

Endocrine manifestations

Thyroid disease is found more commonly in patients with chronic HCV infection than in the general population. About 13% of HCV-infected patients have hypothyroidism and up to 25% have thyroid antibodies. Thyroid disease is found to be one of the most common endocrine disorders in chronic HCV infection (Antonelli 2004). The hypothesis of chronic immune system stimulation in patients with MC who also presented autoimmune thyroiditis is underlined by the elevated levels of CXCL9, CXCL10 and CXCL11 chemokines as well as higher IL-6 levels which can be found in these patients (Ferri 2017). In vitro experiments showed that Hepatitis C virus is even capable of infection of human thyroid cells due to membrane expression of the HCV receptor CD81 (Blackard 2012). There is also evidence that IFN α may induce thyroid disease or unmask preexisting silent thyroidopathies (Graves disease, Hashimoto thyroiditis) (Prummel 2003). Furthermore, the presence of thyroid autoantibodies increases the risk of developing an overt thyroiditis during interferon-based therapy.

The association between chronic HCV infection and development of insulin resistance and diabetes mellitus has been discussed in the past (Knobler 2000, Mason 1999, Hui 2003, Mehta 2003). A meta-analysis of retrospective and prospective studies confirms a higher risk for the development of diabetes mellitus type II in patients with chronic HCV infection (OR=1.68, 95% CI 1.15-2.20) (White 2008). Similar results were reported in a recent prospective study from Taiwan with more than 21000 participants (hazard ratio 1.53, 95% CI 1.29-1.81) (Lin 2016). Viral induction of insulin resistance seems to be HCV-specific, as prevalence of diabetes mellitus in HBV-infected patients is significantly lower (White 2008, Imazeki 2008). The pathomechanism of HCV-induced insulin resistance is yet not fully understood. It has been suggested that the appearance of insulin resistance could correlate with certain genotypes of HCV. By altering host lipid metabolism to favour its own replication, HCV infection leads to hepatic steatosis especially in HCV type 3 infections. Moreover, the occurrence and severity of steatosis correlates with viral load and response to interferon-based therapy in HCV type 3 patients (Rubbia-Brandt 2001). Furthermore, HCV-dependent upregulation of cytokine suppressor SOC-3 may be responsible for the induction of cell desensitisation towards insulin. Peroxisome proliferator-activated receptor-γ coactivator 1α is induced after HCV infection, thereby upregulating gluconeogenesis and providing a potential target for treatment (Shlomai 2012). Insulin resistance in turn represents an independent risk factor for progression of liver fibrosis and lower SVR in patients with chronic HCV infection (Moucari 2008, Kawaguchi 2004).

A causal association is backed up by studies demonstrating that antiviral therapy resulting in SVR correlates with improved diabetic metabolic status and partial resolution of insulin resistance (Kawaguchi 2007, Zhang 2012).

There is growing evidence that a majority of HCV-infected patients also suffer from vitamin D deficiency. Recent clinical data show higher vitamin D levels as an independent predictive factor of SVR following antiviral therapy (Cholongitas 2012). Because of its anti-inflammatory and anti-fibrotic effects, vitamin D supplementation might therefore protect against progression of liver disease (Rahman 2013). HCV-infected patients are at a significantly higher risk of developing osteoporosis and osteoporosis-associated bone fractures. Chronic HCV infection leads to a reduction in bone density due do imbalance in calcium and vitamin D homeostasis and a decreased synthesis of insulin-like growth factor-1 (IGF-1) (Marek 2015). Additionally, it has been shown that bone density decreases with progression of liver fibrosis due to HCV (Lin 2012). In another study with relatively young HCV patients (aged 40 – 60 years) without advanced fibrosis, 42% had reduced bone density and 12% osteoporosis (Lai 2015). Furthermore, a large cohort study from Taiwan with over 10.000 HCV patients and 41.000 controls reported a 1.33-fold increased incidence of osteoporosis in the HCV group versus controls (Chen 2015). Another study from Denmark compared the overall incidence of bone fractures from over 12.000 HCV patients and 60.000 matched controls. HCV patients had a 2.15-fold increased incidence of bone fractures. There was no significant difference in fracture incidence between patients with active versus successfully treated chronic hepatitis C (Hansen 2014).

Finally, a link between HCV, growth hormone (GH) insufficiency and low insulin-like growth factor (IGF1) has been hypothesised. Reduced GH secretion could be the result of a direct inhibitory effect of HCV infection at the level of the pituitary or hypothalamus (Plöckinger 2007).

Cardiovascular manifestations

There is increasing evidence that chronic HCV infection may also increase the risk for cardiovascular diseases. A nearly 1.65-fold increase in cardiovascular disease-related mortality was reported in a large meta-analysis of observational studies. The risk for cerebrovascular or cardiovascular disease in HCV infection was even 1.71-fold higher when additional risk factors like diabetes and arterial hypertension were present (Petta 2016). Moreover, a cohort study from Taiwan found chronic hepatitis C to be an independent predictor of stroke (Negro 2014). Another data from a recent American study with a cohort of 1434 HCV positive participants showed a significantly higher incidence of coronary heart disease events in patients with detectable HCV RNA than in those who were HCV RNA negative (Pothineni 2014). A 1.43-fold increased risk of developing peripheral arterial disease (PAD) in chronically HCV infected Taiwanese patients as compared to uninfected controls might be suggestive that PAD can be regarded as an extrahepatic manifestation of chronic HCV infection (Hsu YH 2015). Potential pathomechanisms might include metabolic factors such as insulin resistance with hyperglycaemia, endothelial dysfunction and inflammation leading to damage of vessels and instability of plaques but also other systemic processes associated with the chronic inflammatory state and potentially leading to atherosclerosis have to be considered (Negro 2015). In addition, chronic HCV infection is independently associated with peripheral arterial stiffness. Compared to controls, HCV patients had increased arterial stiffness with lower compliance indices in a cohort of 221 participants (Chou CH 2017).

First data on DAA therapy effects in patients with advanced liver fibrosis and compensated cirrhosis revealed a significant improvement in carotid atherosclerosis measured by intima media thickness and carotid thickening, although data about major cardiovascular outcomes under DAA therapy are still absent (Petta 2018).A recent nationwide cohort study from Taiwan demonstrated a significant reduction in the incidence of end-stage renal disease, acute coronary syndrome and ischemic stroke in HCV treated patients compared to untreated controls. Treated patients also showed a significant improvement in non-liver death-related survival (see Figure 4, Hsu YC 2015).

Occasionally, chronic HCV infection has been seen in association with other cardiac pathologies such as chronic myocarditis and dilated/hypertrophic cardiomyopathy. Pathogenesis seems to rely on genetic predisposition and is assumed to be immunologically triggered (Matsumori 2000).

Figure 4. A) Overall mortality survival curves for non-liver related causes in treated and untreated patients with chronic HCV infection B) and C) Cumulative incidence of extrahepatic outcomes between treated and untreated HCV cohorts for end-stage renal disease and acute coronary syndrome (according to Hsu YC et al. 2015).

Central nervous manifestations

Numerous central nervous manifestations have been described in association with HCV infection. Cryoglobulinemic or non-cryoglobulinemic vasculitis of cerebral blood vessels may be responsible for the relatively high prevalence of both ischemic and hemorrhagic strokes in young HCV positive patients (Cacoub 1998). Transverse myelopathies leading to symmetrical paraparesis and sensory deficiency have been observed (Aktipi 2007).

Furthermore, chronic HCV infection is associated with significant impairment of quality of life. 35-68% of HCV patients suffer from chronic fatigue, subclinical cognitive impairment and psychomotor deceleration. Symptoms of depression are evident in 2-30% of HCV patients examined (Perry 2008, Forton 2003, Carta 2007). Psychometric as well as functional magnetic resonance spectroscopy studies suggest altered neurotransmission in HCV-infected patients (Weissenborn 2006, Forton 2001). In addition, significant tryptophan deficiency is detectable in patients with chronic HCV infection. Deficiency of tryptophan-derived serotonin is likely to favour an occurrence of depressive disorders. There is evidence to suggest that antiviral therapy can lead to elevation of tryptophan blood levels and thus contribute to amelioration of depressive symptoms in HCV patients (Zignego 2007c).

While the aetiology of cognitive dysfunction in HCV patients is not completely understood, it is hypothesised that the virus has a direct neurotoxic effect by entering the CNS via the PBMCs. This may be accompanied by an indirect neurotoxic effect via cerebral and/or systemic inflammation, for example increased pro-inflammatory cytokines over many years of infection. These cytokines may cross the blood-brain barrier and contribute to cognitive disorders (Senzolo 2011). More recent studies indicate that brain microvascular endothelial cells serve as a preferential site of HCV tropism and replication and that alteration of the blood-brain barrier could lead to activation of microglia and entry of inflammatory cytokines (Fletcher 2012). Supporting new data shows evidence for the affection of mostly memory tasks in HCV-infected children with significant correlations between endogenous cytokines like IL-6 and IFN α and cognitive dysfunction (Abu Faddan 2014).

Significant improvements of mental health and central nervous manifestations (i.e. fatigue and health related quality of life) have been consistently demonstrated during interferon-free DAA-based regimens (Younossi 2014a, Younossi 2014b). A recent study evaluated a significant improvement in health related quality of life due to DAA therapy in patients with cryoglobulinemic vasculitis (Saadoun 2015b). According to recent guidelines (EASL 2018), the presence of such EHM (i.e. debilitating fatigue) should be regarded as a priority treatment indication with DAA, even in the absence of significant liver damage (Negro 2015).

Dermatologic and miscellaneous manifestations

A multitude of cutaneous disorders has been sporadically associated with chronic HCV infection (Hadziyannis 1998). Epidemiologic studies have confirmed the existence of a strong correlation between the sporadic form of porphyria cutanea tarda (PCT) and HCV, though the presence of HCV in PCT patients seems to be subject to strong regional factors. Indeed, HCV prevalence in PCT patients is above 50% in Italy, while only 8% in Germany (Fargion 1992, Stölzel 1995). Because therapy with PEG-IFN and ribavirin may exacerbate the cutaneous manifestations in PCT patients, these individuals might strongly benefit from therapy with DAAs (Negro 2015).

Evidence of a close association between HCV and lichen planus was provided by studies performed in Japan and southern Europe (Nagao 1995, Carrozzo 1996), yet these observations do not apply to all geographic regions (Ingafou 1998). HLA-DR6 has been recognised as a major predisposing factor for development of lichen planus in HCV positive patients. One hypothesis suggests that geographical fluctuation of HLA-DR6 is responsible for the diverse prevalence among HCV patients (Gandolfo 2002). A recent study from Japan showed seven HCV patients with oral lichen planus who were treated with daclatasvir and asunaprevir for 24 weeks. In addition to the SVR24 rate of 100%, the cutaneous manifestations disappeared in four and improved in the remaining three subjects, underlining the close association between replicative HCV infection and oral lichen planus (Nagao 2016).

Recent data from a large cohort of HCV-infected patients showed a higher incidence and mortality for several types of non-liver cancers in individuals with HCV compared to the general population such as pancreas, lung, kidney and rectum malignancies. However it remains elusive if higher smoking rates in the observed HCV cohort could have been a possible confounding factor (Allison 2015). New data from a french population showed only hematological malignancies and oral cancer to be at higher risk in HCV patients compared to the general population. Especially HCV cirrhosis was associated with a higher age-adjusted incidence of non-liver cancers, even after achieving SVR (Allaire 2018).

Idiopathic pulmonary fibrosis (IPF) may potentially be an EHM, as prevalence of anti-HCV in patients with this disease is notably high (Ueda 1992). Interestingly, alveolar lavage in therapy-naïve HCV patients yielded frequent findings consistent with a chronic alveolitis. Alveolar lavage in the same patients after completion of antiviral therapy showed a remission of inflammatory activity (Yamaguchi 1997). Involvement of CGs in the genesis of IPF is also probable (Ferri 1997).

Several ocular abnormalities such as sicca syndrome due to reduced lacrimation as well as a peripheral corneal ulceration which is called Mooren’s ulcer have been reported in association with HCV infection, although the pathogenesis of such abnormalities is not completely understood (Wilson 1993, Tang 2016).

References

Abu Faddan NH, Shehata GA, Abd Elhafeez HA, Mohamed AO, Hassan HS, Abd El Sameea F. Cognitive function and endogenous cytokine levels in children with chronic hepatitis C. J Viral Hepat 2014 Dec 15. doi: 10.1111/jvh.12373. [Epub ahead of print]

Afdhal N, McHutchison J, Brown R, Jacobson I, Manns M, Poordad F, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008;48:1000-7.

Afdhal NH, Dusheiko G, Giannini EG, et al. Final Results of ENABLE 1, a Phase 3, Multicenter Study of Eltrombopag as an Adjunct for Antiviral Treatment of Hepatitis C Virus-Related Chronic Liver Disease Associated With Thrombocytopenia. Hepatology 2011;54:1427-8.

Agnello V, G. Ábel. Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinaemia. Arthritis Rheumatism 1997;40:2007-2015.

Agnello V, De Rosa, FG. Extrahepatic disease manifestations of HCV infection: some current issues. J Hepatol 2004;40:341-352.

Aktipi KM, Ravaglia S, Ceroni M. Severe recurrent myelitis in patients with hepatitis C virus infection. Neurology2007;68:468-9.

Allaire M, Nahon P, Layese R et al. Extra hepatic cancers are the leading cause of death in cirrhotic patients achieving HBV control or HCV eradication. Hepatology 2018 Apr 16. doi: 10.1002/hep.30034.

Allison RD, Tong X, Moorman AC, et al. Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006-2010. J Hepatol 2015;63:822-28.

Alric L, Plaisier E, Thébault S, Péron JM, Rostaing L, Pourrat J, et al. Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN. Am J Kidney Dis 2004;43:617-23.

Antonelli A, Ferri C, Pampana A, et al. Thyroid disorders in chronic hepatitis C. Am J Med 2004;117:10-3.

Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota A, Koida I, et al. Glomerulonephritis in autopsy cases with hepatitis C virus infection. Intern Med 1998;37:836-40.

Arcaini L, Merli M, Passamonti F, Bruno R, Brusamolino E, Sacchi P, et al. Impact of treatment-related liver toxicity on the outcome of HCV positive non-Hodgkin’s lymphomas. 2010;85:45-50.

Aref S, Sleem T, El Menshawy N, Ebrahiem L, Abdella D, Fouda M, et al. Antiplatelet antibodies contribute to thrombocytopenia associated with chronic hepatitis C virus infection. Hematology 2009;14:277-81.

Besson C, Canioni D, Lepage E, Pol S, Morel P, Lederlin P, et al. Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d’Etude des Lymphomes de l’Adulte programs. J Clin Oncol 2006;24:953-60.

Blackard JT, Kong L, Huber AK, Tomer Y. Hepatitis C virus infection of a thyroid cell line: implications for pathogenesis of HCV and thyroiditis. Thyroid 2012;23:863-70.

Bonacci M, Lens S, Londono MC, et al. Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus-Associated Cryoglobulinaemia Treated With Direct-acting Antivirals. Clin Gastroenterol Hepatol 2016. doi:10.1016/j.cgh.2016.09.158.

Boonyapisit K, Katirji B. Severe exacerbation of hepatitis C-associated vasculitic neuropathy following treatment with interferon alpha: a case report and literature review. Muscle Nerve 2002;25:909-13.

Bordin G, Ballare M, Zigrossi P, Bertoncelli MC, Paccagnino L, et al. A laboratory and thrombokinetic study of HCV-associated thrombocytopenia: a direct role of HCV in bone marrow exhaustion? Clin Exp Rheumatol 1995;Suppl 13:S39-43.

Bruchfeld A, Lindahl K, Stahle L, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003;18:1573-80.

Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. New Engl J M 2007;357:2237-47.

Cacoub P, Sbai A, Hausfater P, et al. Central nervous system involvement in hepatitis C virus infection. Gastroenterol Clin Biol 1998;22:631-33.

Cacoub P, Desbois AC, Isnard-Bagnis C, et al. Hepatitis C virus infection and chronic kidney disease: Time for reappraisal. J Hepatol 2016;65:82-94.

Cacoub P, Si Ahmed SN, Ferfar Y, Pol S, Thabut D, Hezode C, Alric L, Comarmond C, Ragab G, Quartuccio L, Hegazy M, Poynard T, Rigon MR, Saadoun D, Longterm Efficacy of Interferon-Free

Antiviral Treatment Regimens in Patients With Hepatitis C Virus-Associated Cryoglobulinaemia Vasculitis, Clinical Gastroenterology and Hepatology 2018;doi: 10.1016/j.cgh.2018.05.021.

Calleja JL, Albillos A, Moreno-Otero R, et al. Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinaemia. Aliment Pharmacol Ther 1999;13:1179-86.

Carrozzo M, Gandolfo S, Carbone M, Colombatto P, Broccoletti R, Garzino-Demo P, et al. Hepatitis C virus infection in Italian patients with oral lichen planus: a prospective case-control study. J Oral Pathol Med 1996;25:527-33.

Carta MG, Hardoy MC, Garofalo A, Pisano E, Nonnoi V, Intilla G, et al. Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy. Clin Pract Epidemol Ment Health 2007;3:22.

Chao TC, Chen CY, Yang YH, et al. Chronic hepatitis C virus infection associated with primary warm-type autoimmune hemolytic anaemia. J Clin Gastroenterol 2001;33:232-33.

Chen CH, Lin CL, Kao CH. Relation Between Hepatitis C Virus Exposure and Risk of Osteoporosis: A Nationwide Population-Based Study. Medicine 2015;94(47):e2086.

Chen YC, Lin HY, Li CY, Lee MS, Su YC. A nationwide cohort study suggests that hepatitis C virus infection is associated with increased risk of chronic kidney disease. Kidney Int 2014;85:1200-7.

Chiao EY, Engels EA, Kramer JR, Pietz K, Henderson L, Giordano TP, Landgren O. Risk of immune thrombocytopenic purpura and autoimmune hemolytic anaemia among 120 908 US veterans with hepatitis C virus infection. Arch Intern Med 2009;169:357-63.

Cholongitas E, Theocharidou E, Goulis J, Tsochatzis E, Akriviadis E, Burroughs AK. Review article: the extra-skeletal effects of vitamin D in chronic hepatitis C infection. Aliment Pharmacol Ther 2012;35:634-46.

Chou CH, Ho CS, Tsai WC et al. Effects of chronic hepatitis C infection on arterial stiffness. J Am Soc Hypertens 2017;11:716-23.

Colantoni A, De Maria N, Idilman R, Van Thiel DH. Polymerase chain reaction for the detection of HCV-RNA: cryoglobulinaemia as a cause for false negative results. Ital J Gastroenterol Hepatol 1997;29:273-77.

Cormier EG, Tsamis F, Kajumo F, Durso RJ, Gardner JP, Dragic T. CD81 is an entry coreceptor for hepatitis C virus. Proc Natl Acad Sci US 2004;101:7270-4.

Craxì A, Laffi G, Zignego AL. Hepatitis C virus (HCV) infection: a systemic disease. Mol Aspects Med 2008;29:85-95.

Daghestani L, Pomeroy C. Renal manifestations of hepatitis C infection. Am J Med 1999;106:347-54.

De Almeida AJ, Campos-de-Magalhaes M, Okawa MY, Vieira de Oliveira R, et al. Hepatitis C virus-associated thrombocytopenia: a controlled prospective, virological study. Ann Hematol 2004;83:434-40.

De la Serna-Higuera C, Bárcena-Marugán R, Sanz-de Villalobos E. Hemolytic anaemia secondary to alpha-interferon treatment in a patient with chronic C hepatitis. J Clin Gastroenterol 1999;28:358-9.

Drugs at FDA. Eltrombopag olamine, NDA 022291. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo

Doutrelepont J-M, Adler M, Willems M, Durez P, Yap SH. Hepatitis C virus infection and membranoproliferative glomerulonephritis. Lancet 1993;341:317.

Duberg AS, Nordström M, Törner A, Reichard O, Strauss R, Janzon R, et al. Non-Hodgkin’s lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection. Hepatology 2005;41:652-59.

European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018;https://doi.org/10.1016/j.jhep.2018.03.026

Fabrizi F, Lunghi G, Messa P, Martin P. Therapy of hepatitis C virus-associated glomerulonephritis: current approaches. J Nephrol 2008;21:813-25.

Fabrizi F, Messa P. Therapy of hepatitis C by direct-acting anti-virals: the end of HCV in dialysis population? Expert Rev Clin Pharmacol 2015;8:785-93.

Fallahi P, Ferrari SM, Giugglioli D et al. Chemokines in the Pathogenesis and as Therapeutical Markers and Targets of HCV Chronic Infection and HCV Extrahepatic Manifestations. Curr Drug

Targets 2017;18:786-93.

Fargion S, Piperno A, Cappellini MD, et al. Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association. Hepatology 1992;16:1322-6.

Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996;24:38-47.

Fernandéz A. An unusual case of autoimmune hemolytic anaemia in treatment naïve hepatitis C virus infection. Hematology 2006;11:385-87.

Ferri C, La Civita L, Fazzi P, Solfanelli S, Lombardini F, Begliomini E, et al. Intestinal lung fibrosis and rheumatic disorders in patients with hepatitis C virus infection. Br J Rheumatol 1997;36:360-65.

Ferri C, Sebastiani M, Guiggiolo D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinaemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum 2004;33:355-74.

Ferri C, Antonelli A, Mascia M.T, et al. B cells and mixed cryoglobulinaemia. Autoimmun Rev 2007;7:114-20.

Ferri C, Ramos-Casals M, Zignego AL, et al. International diagnostic guidelines for patients with HCV-related extrahepatic manifestations. A multidisciplinary expert statement. Autoimmun Rev 2016;15:1145-60.

Ferri C, Colaci M, Fallahi P et al. Thyroid involvement in Hepatitis C Virus-Infected Patients with/without Mixed Cryoglobulinaemia. Front Endocrinol (Lausanne) 2017; 8:159. doi: 10.3389/fendo.2017.00159.

Flemming JA, Lowe CE. Successful treatment of hepatitis C, genotype 3, with sofosbuvir/ledipasvir in decompensated cirrhosis complicated by mixed cryoglobulinaemia. BMJ Case Rep 2016;pii: bcr2016215293. doi: 10.1136/bcr-2016-215293.

Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, et al. Hepatitis C Virus Infects the Endothelial Cells of the Blood-Brain Barrier. Gastroenterol 2012;142:634-43.

Forton DM, Allsop JM, Main J, et al. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001;358:38-9.

Forton DM, Taylor-Robinson SD, Thomas HC. Cerebral dysfunction in chronic hepatitis C infection. J Viral Hepat 2003;10:81-6.

French Association for the Liver Study (AFEF). AFEF recommendations on the management of viral hepatitis C. 2016.

Gandolfo S, Carrozzo M. Lichen planus and hepatitis C virus infection. Minerva Gastroenterol Dietol 2002;48:89.

García-Suárez J, Burgaleta C, Hernanz N, Albarran F, Tobaruela P, Alvarez-Mon M. HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy. Br J Haematol 2000;110:98-103

Garini G, Allegri L, Lannuzzella F, Vaglio A, Buzio C. HCV-related cryoglobulinemic glomerulonephritis: implications of antiviral and immunosuppressive therapies. Acta Biomed 2007;78:51-9.

Giannelli F, Moscarella S, Giannini C, Caini P, Monti M, et al. Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation. Blood 2003;102:1196-201.

Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H, Engels EA. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA 2007;297:2010-7.

Gragnani L, Fabbrizzi A, Triboli E, et al. Triple antiviral therapy in hepatitis C virus infection with or withput mixed cryoglobulinaemia: A prospective, controlled pilot study. Dig Liver Dis 2014;46:833-7.

Gragnani L, Fognani E, Piluso A, et al. Long-Term Effect of HCV Eradication in Patients With Mixed Cryoglobulinaemia: A Prospective, Controlled, Open-Label, Cohort Study. Hepatology 2015;61:1145-53.

Gragnani L, Visentini M, Fognani E, et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis c virus-associated mixed cryoglobulinaemia. Hepatology 2016;64:1473-82.

Hadziyannis SJ. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol 1998;10:12-21.

Hansen AB, Omland LH, Krarup H, Obel N; DANVIR cohort study. Fracture risk in hepatitis C virus infected persons: results from the DANVIR cohort study. J Hepatol 2014;61(1):15-21.

Hegazy MT, Hussein MA, Quartuccio L, Fawzy M, Zoheir N, Ellawindi MI, et al. Treatment of Cryoglobulinemic Vasculitis with Sofosbuvir in Four Combination Protocols [abstract]. Arthritis

Rheumatol 2016;68(suppl 10).

Hui JM, Sud A, Farrell GC, Bandara P, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology 2003;125:1695-704.

Hundemer GL, Sise ME, Wisocky J, et al. Use of sofosbuvir-based direct-acting antiviral therapy for hepatitis C viral infection in patients with severe renal insufficiency. Infect Dis (Lond) 2015;47:924-9.

Hsu YC, Ho HJ, Huang YT, et al. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut 2015;64:495-503.

Hsu YH, Muo CH, Liu CY, et al. Hepatitis C virus infection increases the risk of developing peripheral arterial disease: A 9-year population-based cohort study. J Hepatol 2015;62:519-25.

Iga D, Tomimatsu M, Endo H, Ohkawa S-I, Yamada O. Improvement of thrombocytopenia with disappearance of HCV RNA in patients treated by interferon-a therapy: possible aetiology of HCV-associated immune thrombocytopenia. Eur J Haematol 2005;75:417-23.

Imazeki F, Yokosuka O, Fukai K, Kanda T, Kojima H, Saisho H. Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver international 2008;28:355-62.

Ingafou M, Porter SR, Scully C, Teo CG. No evidence of HCV infection or liver disease in British patients with oral lichen planus. Int J Oral Maxillofac Surg 1998;27:65-6.

Kamar N, Rostaing L, Alric L. Treatment of hepatitis C-virus-related glomerulonephritis. Kidney Int 2006;69:436-9.

Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol 2004;165:1499-508.

Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, ß-cell function, and hepatic expression of insulin receptor substrates 1 and 2. Am J Gastroenterol 2007;102:1-7.

Khiani V, Kelly T, Adeel S, Jensen D, Mohanty SR. Acute inflammatory demyelinating polyneuropathy associated with pegylated interferon a 2a therapy for chronic hepatitis C virus infection. World J Gastroenterol 2008;14:318-21.

Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc 2000;75:355-9.

Koskinas J, Kilidireas C, Karandreas N, Kountouras D, Savvas S, et al. Severe hepatitis C virus-related cryoglobulinaemic sensory-motor polyneuropathy treated with pegylated interferon-a2b and ribavirin: clinical, laboratory and neurophysiological study. Liver Int 2007;27:414-20.

Lai JC, Shoback DM, Zipperstein J, et al. Bone Mineral Density, Bone Turnover, and Systemic Inflammation in Non-cirrhotics with Chronic Hepatitis C. Dig Dis Sci 2015;60(6):1813-19.

Levine JW, Gota C, Fessler BJ, et al. Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. J Rheumatol 2005;32:1164-7.

Lidove O, Cacoub P, Maisonobe T, Servan J, Thibault V, Piette JC, et al. Hepatitis C virus infection with peripheral neuropathy is not always associated with cryoglobulinaemia. Ann Rheum Dis 2001;60:290-2.

Lin JC, Hsieh TY, Wu CC, et al. Association between chronic hepatitis C virus infection and bone mineral density. Calcif Tissue Int 2012;91(6):423-9.

Lin YJ, Shaw TG, Yang HI, et al. Chronic hepatitis C virus infection and the risk for diabetes: a community-based prospective study. Liver Int 2016 Jul 1. doi: 10.1111/liv.13194.

Lunel F, Musset L, Cacoub P, Franguel L, Cresta P, Perri M, et al. Cryoglobulinaemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 1994;106:1291-300.

Machida K, Cheng KT, Sung VM, Shimodaira S, Lindsay KL, et al. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci USA 2004;101:4262-7.

Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999;29:328-33.

Marek B, Kajdaniuk D, Niedziołka D, et al. Growth hormone/insulin-like growth factor-1 axis, calciotropic hormones and bone mineral density in young patients with chronic viral hepatitis. Endokrynol Pol 2015;66(1):22-9

Margin S, Craxi A, Fabiano C, et al. Hepatitis C viraemia in chronic liver disease: relationship to interferon alpha or corticosteroid treatment. Hepatology 1994;19:273-9.

Matsumori A, Yutani C, Ikeda Y, Kawai S, Sasayama S. Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy. Lab Invest 2000;80:1137-42.

Matsuo K, Kusano A, Sugumar A, Nakamura S, Tajima K, Mueller NE. Effect of hepatitis C virus infection on the risk of non-Hodgkin’s lymphoma: a meta-analysis of epidemiological studies. Cancer Sci 2004;95:745-52.

Mauss S, Hueppe D, Alshuth U.Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. Hepatology 2014;59:46-8.

McGuire BM, Julian BA, Bynon JS Jr, Cook WJ, King SJ, Curtis JJ, et al. Brief communication: Glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation. Ann Intern Med 2006;144:735-41.

McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007;357:2227-36.

Mele A, Pulsoni A, Bianco E, Musto P, Szklo A, Sanpaolo MG, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood 2003;102:996-9.

Mehta SH, Brancati FL, Strathdee SA, Pankow JS, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology 2003;38:50-6.

Molnar MZ, Alhourani HM, Wall BM, et al. Association of Hepatitis C Viral Infection With Incidence and Progression of Chronic Kidney Disease in a Large Cohort of US Veterans. Hepatology 2015;61:1495-502.

Moucari R, Asselah T, Cazals-Hatem D, Voitot H, et al. Insulin resistance in chronic hepatitis C: Association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008;134:416-23.

Nagao Y, Sata M, Tanikawa K, Itoh K, Kameyama T. Lichen planus and hepatitis C virus in the northern Kyushu region of Japan. Eur J Clin Invest 1995;25:910-4.

Nagao Y, Kimura K, Kawahigashi Y, Sata M. Successful Treatment of Hepatitis C Virus-associated Oral Lichen Planus by Interferon-free Therapy with Direct-acting Antivirals. Clin Transl Gastroenterol 2016;7:e179.

Negro F. Facts and fictions of HCV and comorbidities: Steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol 2014;61:69-78.

Negro F, Forton D, Craxi A, et al. Extrahepatic Morbidity and Mortality of Chronic Hepatitis C. Gastroenterology 2015;149:1345-60.

Nomura H, Tanimoto H, Kajiwara E, Shimono J, Maruyama T, Yamashita N, et al. Factors contributing to ribavirin-induced anaemia. J Gastroenterol Hepatol 2004;19:1312-7.

Paydas S, N. Seyrek, G. Gonlusen, Y. Sagliker. The frequencies of hepatitis B virus markers and hepatitis C virus antibody in patients with glomerulonephritis. Nephron 1996;74:617-9.

Perry W, Hilsabeck RC, Hassanein TI. Cognitive dysfunction in chronic hepatitis C: a review. Dig Dis Sci 2008;53:307-21.

Petrarca A, Rigacci L, Caini P, et al. Safety and efficacy of rituximab in patients with hepatitis C virus-related mixed cryoglobulinaemia and severe liver disease. Blood 2010;116:335-42.

Petta S, Maida M, Macaluso FS, et al. Hepatitis C Virus Infection Is Associated With Increased Cardiovascular Mortality: A Meta-Analysis of Observational Studies. Gastroenterology 2016:doi:10.1053/j.gastro.2015.09.007.

Petta S, Adinolfi LE, Fracanzani AL, et al. Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis. J Hepatol

2018;https://doi.org/10.1016/j.jhep.2018.02.015

Plöckinger U, Krüger D, Bergk A, Weich V, Wiedenmann B, Berg T. Hepatitis-C patients have a reduced growth hormone (GH) secretion which improves during long-term therapy with pegylated interferon-a. Am J Gastroenterol 2007;102:2724-31.

Pothineni NVKC, Delongchamp R, Vallurupalli S, et al. Impact of hepatitis C seropositivity on the risk of coronary heart disease events. Am J Cardiol 2014;114:1841-5.

Prummel MF, Laurberg P. Interferon-alpha and autoimmune thyroid disease. Thyroid 2003;13:547-51.

Rahman AH, Branch AD. Vitamin D for your patients with chronic hepatitis C? J Hepatol 2013;58:184-9.

Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol 2005;129:818-24.

Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet 2012;379:348-60.

Ray RB, Meyer K, Ray R. Suppression of apoptotic cell death by hepatitis C virus core protein. Virology 1996;226:176-82.

Roccatello D, Baldovino S, Rossi D, Mansouri M, Naretto C, et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant 2004;19:3054-61.

Roccatello D, Baldovino S, Rossi D, Giachino O, Mansouri M, et al. Rituximab as a Therapeutic Tool in Severe Mixed Cryoglobulinaemia. Clin Rev Allergy Immunol 2008;34:111-7.

Rollino C., D. Roccatello, O Giachino, B. Basolo, G. Piccoli. Hepatitis C virus Infection and membranous glomerulonephritis. Nephron 1991;59:319-20.

Roque Afonso AM, Jiang J, Penin F, Tareau C, Samuel D, Petit MA, et al. Nonrandom distribution of hepatitis C virus quasispecies in plasma and peripheral blood mononuclear cell subsets.J Virol 1999;73:9213-21.

Rubbia-Brandt L, Giostra E, Mentha G, Quadri G, Negro F Expression of liver steatosis in hepatitis C virus infection and pattern of response to α-interferon. J Hepatol 2001;35:307.

Saadoun D, Asselah T, Resche-Rigon M, Bedossa P, Valla D, et al. Cryoglobulinaemia is associated with steatosis and fibrosis in chronic hepatitis C. Hepatology 2006;43:1337-45.

Saadoun D, Resche-Rigon M, Sene D, Perard L, Piette JC, Cacoub P. Rituximab combined with Peg-Interferon-Ribavirin in refractory HCV-associated cryoglobulinaemia vasculitis. Ann Rheum Dis 2008;67:1431-36.

Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 2011;365:2067-77.

Saadoun D, Resche Rigon M, Pol S, et al. PegIFNα/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinaemia vasculitis. J Hepatol 2015a;62:24-30.

Saadoun D, Thibault V, Si Ahmed SN, et al. Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Ann Rheum Dis 2015b:1-6.

Saadoun D, Pol, S, Ferfar Y et al. Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinaemia Vasculitis. Gastroenterol 2017;153:49-52.

Sabry AA, Sobh MA, Sheaashaa HA, Kudesia G, Wild G, Fox S, et al. Effect of combination therapy (ribavirin and interferon) in HCV-related glomerulopathy. Nephrol Dial Transplant 2002;17:1924-30.

Sakamuro D, Furukawa T, Takegami T. Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J Virol 1995;69:3893-6.

Sansonno D, Gesualdo L, Manno C, Schena FP, Dammacco F. Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology 1997;25,1237-44.

Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinaemia resistant to interferon alpha with an anti-CD20. Blood 2003;101:3818-26.

Senzolo M, Schiff S, D’Aloiso CM, Crivellin C, Cholongitas E, Burra P, et al. Neuropsychological alterations in hepatitis C infection: The role of inflammation. World J Gastroenterol 2011;17:3369-74.

Shlomai A, Rechtman MM, Burdelova EO, Zilberberg A, Hoffman S, Solar I, et al. The metabolic regulator PGC-1α links hepatitis C virus infection to hepatic insulin resistance. J Hepatol 2012;57:867-73.

Silvestri F, Barillari G, Fanin R, Pipan C, Falasca E, Salmaso F, et al. Hepatitis C virus infection among cryoglobulinemic and non-cryoglobulinemic B-cell non-Hodgkin’s lymphomas. Haematologica 1997;82:314-7.

Sise ME, Bloom AK, Wisocky J et al. Treatment of Hepatitis C Virus-Associated Mixed Cryoglobulinaemia with Direct-Acting Antiviral Agents. Hepatology 2015;doi: 10.1002/hep.28297.

Srinivasan R. Autoimmune hemolytic anaemia in treatment naïve chronic hepatitis C infection. J Clin Gastroenterol 2001;32:245-7.

Stölzel U, Köstler E, Koszka C, Stöffler-Meilicke M, Schuppan D, Somasundaram R, et al. Low prevalence of hepatitis C virus infection in porphyria cutanea tarda in Germany. Hepatology 1995;21:1500-3.

Tang L, Marcell L, Kottilil S. Systemic manifestations of hepatitis C infection. Infect Agent Cancer 2016;11:29. doi: 10.1186/s13027-016-0076-7.

Takehara K, Otsuka T, Arai T, Matsuzaki Y, et al. Detection of hepatitis C virus (HCV) in platelets of type C chronic liver diseases by polymerase chain reaction (PCR). Gastroenterology 1994;106:A995.

Tarantino A, Campise M, Banfi G, Confalonieri R, Bucci A, Montoli A, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 1995;47:618-23.

Tembl JI, Ferrer JM, Sevilla MT, Lago A, Mayordomo F, Vilchez JJ. Neurologic complications associated with hepatitis C virus infection. Neurology 1999;19:889-95.

Ueda T, Ohta K, Suzuki N, Yamaguchi M, Hirai K, et al. Idiopathic pulmonary fibrosis and high prevalence of serum antibodies to hepatitis C virus. Am Rev respire Dis 1992;146:266-8.

Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, et al. 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 2005;23:468-73.

van Leusen R, Adang RP, de Vries RA, Cnossen TT, Konings CJ, Schalm SW, Tan AC. Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transplant 2008;23:721-5.

Vigano M, Lampertico P, Rumi MG, Folli C, Maggioni L, et al. Natural history and clinical impact of cryoglobulins in chronic Hepatitis C: 10-year prospective study of 343 patients. Gastroenterology 2007;133:835-42.

Wang CS, Yao WJ, Wang ST, Chang TT, Chou P. Strong association of Hepatitis C virus (HCV) infection and thrombocytopenia: implications from a survey of a community with hyperendemic HCV infection. Clin Infect Dis 2004;39:790-6.

Weiner SM, Berg T, Berthold C, Weber S, Peters T, Blum H, et al. A clinical and virological study of hepatitis C virus-related cryoglobulinaemia in Germany. J Hepatol 1998;29:375-84

Weissenborn K, Ennen JC, Bokemeyer M, Ahl B, Wurster U, Tillmann H, et al. Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut. 2006;55:1624-30.

Weitz IC. Treatment of immune thrombocytopenia associated with interferon therapy of hepatitis C with the anti-CD20 monoclonal antibody, rituximab. Am J Hematol 2005;78:138-41.

White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: A systematic review and meta-analysis. J Hepatol 2008;49:831-44.

Wilson SE, Lee WM, Murakami C, et al. Mooren’s corneal ulcers and hepatitis C virus infection. N Engl J Med 1993;329:62.

Wintrobe M, Buell M. Hyperproteinemia associated with multiple myeloma. With report of a case in which extraordinary hyperproteinemia was associated with thrombosis of the retinal veins and symptoms suggesting Raynoud’s disease. Bull Johns Hopkins Hosp 1933;52:156-65.

Wang RY, Bare P, De Giorgi V, et al. Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system. Hepatology 2016;64:1900-10.

Wong VS, Egner W, Elsey T, Brown D, Alexander GJ. Incidence, character and clinical relevance of mixed cryoglobulinaemia in patients with chronic hepatitis C virus infection. Clin Exp Immunol 1996;104:25-31.

Yamaguchi S, Kubo K, Fujimoto K, Hanaoka M, Hayasaka M, et al. Bronchoalveolar lavage fluid findings in patients with chronic hepatitis C before and after treatment with interferon alpha. Thorax 1997;52:33-7.

Younossi ZM, Stepanova M, Gerber L, et al. Improvement of central fatigue is associated with sustained virologic response (SVR) following sofosbuvir (SOF) containing regimens. J Hepatol 2014a;60(suppl):S308.

Younossi ZM, Stepanova M, Henry L. et al. Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C). J Hepatol 2014b;60:741-7.

Zhang W, Rao HY, Feng B, Liu F, Wei L. Effects of Interferon-Alpha Treatment on the Incidence of hyperglycaemia in Chronic Hepatitis C Patients: A Systematic Review and Meta-Analysis. PloS One 2012;7:e39272.

Zignego AL, Macchia D, Monti M, Thiers V, Mazzetti M, Foschi M, et al. Infection of peripheral mononuclear blood cells by hepatitis C virus. J Hepatol 1992;382-6.

Zignego AL, Giannelli F, Marrocchi ME, Mazzocca A, Ferri C, Giannini C, et al. T(14;18) translocation in chronic hepatitis C virus infection. Hepatology 2000;31:474-9.

Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB. Extrahepatic manifestations of the Hepatitis C Virus infection: a general overview and guidelines for clinical approach. Dig Liver Dis 2007a;39:2-17.

Zignego AL, Giannini C, Ferri C. Hepatitis C virus-related lymphoproliferative disorders: an overview. World J Gastroenterol 2007b;13:2467-78.

Zignego AL, Cozzi A, Carpenedo R, Giannini C, Rosselli M, Biagioli T, et al. HCV patients, psychopathology and tryptophan metabolism: analysis of the effects of pegylated interferon plus ribavirin treatment. Dig Liver Dis 2007c;39:107-11.

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