13. 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).

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).

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. There seems to be 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). A meta-analysis of seven studies with over 10.000 patients found a higher incidence of B-cell NHL associated with HCV infection (De Sanjose 2008). The most prevalent HCV-associated lymphoproliferative disorders according to the REAL/WHO classification are: follicular lymphoma, B cell chronic lymphocytic leukemia/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).

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. Moreover, there are only few systematic studies on the effect of SVR caused by DAA therapy on EHMs (Younossi 2016). 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.

In the treatment era of DAA regimens, several prospective studies 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). Furthermore, recent data show the benefit of viral clearance induced by DAA therapy on liver- and non-liver-related mortality compared to matched untreated controls (Negro 2019). 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). In another large retrospective cohort of DAA-treated patients, a successful treatment with SVR was associated with significant risk reduction of developing MC, glomerulonephritis and lichen planus, but no significant effect on the risk of diabetes and NHL (El-Serag 2019).

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 cryoglobulinemia has been established, the therapeutic approach of symptomatic mixed cryoglobulinemia 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). The amount of the clinical benefit of HCV therapy seems to be inversely correlated with the time from diagnosis to initiation of antiviral therapy, which favors an early start of treatment (Mahale 2018). A therapeutic limitation seems to be the possible persistence of B-cell clones in a dormant state long after HCV eradication has been established, as there is a risk of reactivation leading to recurrent cryoglobulinemia syndrome (Visentini 2019). 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). Rituximab has been shown to be an effective and safe treatment option for MC even in advanced liver disease. Moreover, B cell depletion can lead to improvement ofcirrhotic syndrome by mechanisms that remain to be elucidated (Petrarca 2010).

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 cryoglobulinemia-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 interferon-free antiviral treatment options, 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 a SVR12 rate of 83%. Interestingly, treatment response was associated with an improvement in eGFR and a reduction in proteinuria (Sise 2015). In severe mixed cryoglobulinemia-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). Another long-term follow-up analysis investigated 148 patients with HCV-associated CV who were treated with different DAA regimens (sofosbuvir+daclatasvir, sofosbuvir+RBV, sofosbuvir+ledipasvir or sofosbuvir+simeprevir) for 12 or 24 weeks. More than 95 % of patients achieved a full or partial response of CV symptoms following DAA therapy (Cacoub 2019).

Therefore, studies with DAA therapy have shown discordant rates regarding SVR and CV response rates (Sise 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

Cryoglobulinemia-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. 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 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 2019).

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.

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 viremia. 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). Recent data also show the concomitance of DAA therapy and chemotherapy to be safe and effective in influencing remission of high-grade NHL in HCV patients with a higher disease-free survival in treated HCV patients with aggressive NHL (Persico 2018).

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 another 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, hyperlipidemia 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 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). According to the recently revised KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, all patients with chronic kidney disease should be tested for the presence of HCV infection and all HCV patients should be assessed for kidney damage (Kidney International Supplements 2018).

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 viremia 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 anemia (Fabrizi 2008). RBV-induced hemolytic anemia 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. Data from a recent cohort of 101 HCV patients with chronic kidney disease stage 3b, 4 or 5 treated with glecaprevir/pibrentasvir showed an SVR rate of 97% (98/101) with no virologic failure and no safety signals, which support the use of this regimen in HCV patients with advanced and end-stage renal disease (Lawitz 2019). Currently, grazoprevir plus elbasvir is the recommended therapeutic regimen in HCV type 1 patients with severe or terminal renal insufficiency (AFEF 2016).

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). As the development of insulin resistance or type 2 diabetes mellitus may contribute to the progression of liver disease during HCV infection, some international guidelines recommend that antiviral treatment should be promptly initiated in HCV infected patients with insulin resistance or diabetes (Cacoub 2018).

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 disease. Many direct and indirect factors which contribute to the development of atherosclerosis and cardiovascular disease have been identified, such as insulin resistance, oxidative stress, lipopolysaccharides and proinflammatory cytokines (see Figure 4, Adinolfi 2018). 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 hyperglycemia, 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 2017).

However SVR in HCV infection results in an increase in total and LDL cholesterol, which seems contradictory to the data reported above (Mauss 2017). The interaction of terminating a possibly proatherogenic chronic infection which results in an increase of proatherogenic lipids requires further research to draw a clinical relevant concusion.

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 5, Hsu YC 2015). The current available data show that the eradication of HCV by DAA therapy is associated with an improvement of atherosclerosis and metabolic conditions which may lead to the development of cardiovascular disease at least in the short term and at early disease stages, yet further studies are needed to clarify these results (Adinolfi 2018).

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).

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 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).

Miscellaneous manifestations

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). A higher prevalence of extrahepatic malignancies than expected was also found in a cohort of 431 HCV patients who were treated with DAAs in Israel. The incidence of lymphoma was about 100 times higher than in the general population. Also, the incidence of pancreatic, endocervix, breast and squamous cell lung carcinoma increased 29-, 1.6-, 136- and 2,5-fold, respectively. One possible cause might be down-regulating of immune response after successful DAA therapy with higher vulnerability to the development of neoplasia, yet larger multicentered studies are required to confirm these results (Khoury 2019).

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).

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