Book on hepatitis from page 272 to 281

Book on hepatitis from page 272 to 281

272  Hepatology 2012
16. Extrahepatic Manifestations of Chronic
HCV
Karl-Philipp Puchner, Albrecht Böhlig and Thomas Berg
Introduction
Patients with chronic hepatitis C virus (HCV) infection are at risk of a great number
of extrahepatic manifestations (EHMs) (Table 1) –  up to 40-76% of patients
infected with HCV develop at least one EHM during the course of the disease
(Cacoub 2000, Cacoub 1999). EHMs may often be the first and only clinical sign of
chronic hepatitis C infection. Evidence of HCV infection should always be sought
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
cryoglobulinemia, particular lymphotropism of the virus, molecular mimicry and
non-cryoglobulinemic autoimmune phenomena constitute the major pathogenic
factors (Ferri 2007). Nevertheless, pathogenesis and epidemiology of many EHMs
requires 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 cryoglobulinemia
Cryoglobulinemia 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, on the basis of their clonality, into three types (Table 2). Type II CG and
type III CG, consisting of monoclonal and/or polyclonal immunoglobulins, are
prevalent in patients with a 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 cryoglobulinemia is found in 19%-50% of patients with chronic HCV, but leads to clinical manifestations, through
Extrahepatic Manifestations of Chronic HCV  273
vascular precipitation of immunocomplexes, in only 30% of them (Lunel 1994;
Wong 1996). Asymptomatic mixed cryoglobulinemia, during the course of chronic
HCV infection, may evolve into symptomatic disease. Patients with symptomatic
mixed cryoglobulinemia exhibit higher cryoglobulin concentrations (cryocrit >3%)
(Weiner 1998) and lower concentrations of complement factors C3 and C4. Thus
CG-triggered complement activation may constitute a key incidence in
cryoglobulinemia-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  •  Autoimmune thyroidopathies
(in particular, Hashimoto thyroiditis)
•  Insulin resistance/diabetes mellitus*
•  GH-insufficiency
•
Rheumatic disorders •  Mixed cryoglobulinemia*
•  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 anemia
Dermatologic disorders   •  Palpable purpura
•  Porphyria cutanea tarda (PCT)
•  Lichen planus
•  Pruritus
Miscellaneous  •  Chronic fatigue*, subclinical cognitive impairment,
psychomotoric deceleration, symptoms of depression*
•  Myopathy
•  Cardiomyopathy/Myocarditis
•  Idiopathic pulmonal fibrosis
* Associations that rest upon strong epidemiological prevalence and/or clear pathogenetic
mechanisms.
274  Hepatology 2012
Table 2. Types of cryoglobulinemia.
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
D
C
B
A
MC-relateddisorders
Lymphoproliferative
disorders
Diabetes
mellitus II
Lichen
planus
Porphyriacutanea
tarda
Thrombocytopenia
Autoimmune
thyroiditis
Siccasyndrom
Idiopaticpumlmonaryfibrosis
GH-Insuffiency
Non-cryoglobulinaemicGN
Non-cryogloblinaemic
neuropathies
Rheumatoid
arthritis Myocarditis
Myopathy
Autoimmune haemolyticanaemia
Figure 1. Schematic representation of EHM categories (modified after Zignego 2007a). A)
Associations with strong epidemiological evidence and clear pathogenetic mechanisms; B)
Associations with high prevalence, but unclear pathogenetic mechanisms; C) Associations for
which the high prevalence in HCV collectives could be due to HCV infection and/or confounding
factors; D) Anecdotal observations.
Diagnosis
Detection of CG is carried out by keeping patient serum at 4°C for up to 7 days.
After cryoprecipitate is visible, CG can be purified and characterized using
immunfixation electrophoresis. In case of evidence of mixed cryoglobulinemia in
HCV-positive patients, the presence of cryoglobulinemic syndrome must be sought.
Vigilant monitoring is required, as asymptomatic mixed cryoglobulinemia 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).
Extrahepatic Manifestations of Chronic HCV  275
Table 3. Diagnostic criteria of cryoglobulinemic syndrome.
Serologic  Histopathologic  Clinical
•  C4 reduction
•  Positive rheumatoid factor
(RF)
•  CGs type II or III
•  HCV antibodies
•  Leukocytoclastic vasculitis
•  Infiltrates of monoclonal B-cells
•  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 parameter 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 cryoglobulinemia 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 cryoglobulinemia is the
membranous proliferative glomerulonephritis (MPGN), characterized 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
towards 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 cryoglobulinemia. MC-related neuropathy,
presenting clinically as mononeuropathy or polyneuropathy, is mostly sensory and
is characterized by numbness, burning skin crawling 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
cryoglobulinemia (Ferri 2004).
276  Hepatology 2012
Cirrhosis
The causal association between CG and progression of liver fibrosis suggested by
numerous authors has not been confirmed in a recently 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).
With respect to this data, it is unlikely that mixed cryoglobulinemia 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 twofold
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 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.
HCV-associated lymphoproliferative disorders (LPDs) are observed over the
course of MC. 8-10% of mixed cryoglobulinemia 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 cryoglobulinemia (Silvestri 1997).
Genetic predisposition and other factors seem to have a major impact on the
development of LPDs in HCV-positive patients (Matsuo 2004).
Etiology 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 the very invasion of HCV 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 envisioned (Zignego 2000, Machida 2004).
Extrahepatic Manifestations of Chronic HCV  277
Fig 2. Pathomechanisms involved in the development of malignant lymphoproliferative
disorders in patients with chronic HCV infection. Indirect pathomechanism: Sustained
antigen stimulation, like binding of viral envelope protein to CD81 receptor, leads to excessive
B cell proliferation, which in turn favors development of mixed cryoglobulinemia and/or genetic
aberrations, such as t(14;18) translocation. Direct pathomechanism: Viral infection of B cells, as
viral replication in them may result in activation of proto-oncogenes (i.e., Bcl-2) and/or inhibition
of apoptotic factors (i.e., p53, c-myc). One of the factors favoring this polyclonal B cell activation
and proliferation is probably the HCV E2 protein, which binds specifically to CD81, a potent B
cell activator (Cormier 2004).
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. The protease inhibitors boceprevir and telaprevir have been shown to
improve significantly sustained virologic response rate in HCV type 1-infected
patients when given in combination with peg-interferon plus ribavirin as compared
to peg-interferon and ribavirin alone, and can be therefore regarded as the treatment
of choice in HCV type 1-infected patients with extrahepatic manifestations.
However, certain protease-inhibitor-associated contraindications, especially drug-drug interaction due to their metabolism via the CYP3A isoenzymes, have to be
taken into account and all concomitant medications need to be assessed and
adjusted. For further information, see the other HCV chapters.
Mixed cryoglobulinemia
While asymptomatic MC per se does not constitute an indication for treatment,
symptomatic mixed cryoglobulinemia should always be treated. Because
asymptomatic cryoglobulinemia may evolve into symptomatic in the course of
278  Hepatology 2012
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.
Indeed, clinical improvement of MC is reported in 50 to 70% of patients receiving
antiviral therapy with IFN α and RBV and mostly correlates with a drastic reduction
of HCV RNA concentrations (Calleja 1999). However, cryoglobulinemic vasculitis
following successful antiviral treatment persists in a small collective (Levine 2005).
IFN α has been shown to be a promising therapeutic tool irrespective of virologic
response. Due to its antiproliferative properties on IgM-RF producing B cells and
stimulation of macrophage-mediated clearance of immunocomplexes, IFN α may
lead to clinical amelioration even in virological  nonresponders. Therefore,
therapeutic success should be primarily evaluated on the basis of clinical response
irrespective of virologic response. In case of treatment failure of antiviral therapy
and/or fulminant manifestations, contraindications or severe side effects, alternative
therapeutic strategies such as cytostatic immunosuppresive therapy and/or
plasmapheresis should be considered (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 further studied (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 also 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 light of this, combined application
of rituximab with PEG-IFN  α  plus ribavirin in cases of severe mixed
cryoglobulinemia-related vasculitis resistant to antiviral therapy seems to be the
optimal therapeutic strategy, achieving amelioration of MC-related symptoms and a
complete eradication of HCV in responders (Saadoun 2008). In severe rituximab-refractory mixed cryoglobulinaemia-related vasculitis or acute manifestations,
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).
Peripheral neuropathy
Effectiveness of antiviral therapy on cryoglobulinemic-induced peripheral
neuropathy is still being debated. While HCV-related peripheral neuropathy
responsive to antiviral therapy with IFN α and 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 occurance of demyelinating
polyneuropathy during IFN α and PEG-IFN α treatment (Boonyapist 2002, Khiani
2008). Therefore, application of IFN α in presence of HCV-related neuropathy
requires a cautious risk-benefit assessment.
Extrahepatic Manifestations of Chronic HCV  279
Figure 3. Therapy algorithm for symptomatic HCV-related mixed cryoglobulinemia
(modified from Craxi 2008). Antiviral therapy, on the basis of PEG-IFN α and ribavirin
plus/minus protease inhibitors, is regarded as first line therapy in cases of mild/moderate
manifestations. In case of contraindications, patients should be treated primarily with
corticosteroids. Non-response to antiviral therapy or drug-induced aggravation makes
application of corticosteroids essential. 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 elevation is minor. In
patients with severe manifestations, treatment should focus on immunosupression (±
plasmapheresis). Due to its excellent immunosuppressive properties and relatively mild side
effect profile, use of rituximab should be favored. In case of good clinical response, consecutive
antiviral treatment with PEG-IFN α and ribavirin may serve as maintenance therapy. Therapy
refractory cases require individual treatment according to the particular center’s experience.
Supplementation of therapeutic strategy with antiviral therapy should be considered.
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. PEG-IFN  α  plus
ribavirin (± protease inhibitors) should be regarded in such cases as first-line
therapy (Giannelli 2003, Vallisa 2005). Thus, remission of the hematologic
disorders is closely associated with virologic response or rather achievement of
sustained virologic response. Effectiveness of IFN α in this context should be
ascribed primarily to the drug’s antiviral and less to its anti-proliferative properties.
280  Hepatology 2012
Table 4. Treatment of cryoglobulinemia-related disorders in patients with chronic HCV
infection.
Author  Patients  Treatment  Result
Zuckerman   N=9
symptomatic-MC
non-responders to
IFN α monotherapy
IFN α 3x/wk
+ ribavirin 15 mg/kg/d
CGs undetectable within
6 weeks in 7/9 patients;
clinical improvement in
9/9 within 10 weeks
Sansonno   N=20
MC vasculitis and
peripheral neuropathy
resistant to IFN α
montherapy
Rituximab 375 mg/m
2
/
4x/wk
16 patients complete
clinical response;12
sustained response
throughout follow-up.
Viremia increase in
responders.
Saadoun   N=16
MC vasculitis in
relapsers or non-responders to IFN
α/PEG-IFN α + RBV
Rituximab 375 mg/m
2
/
4x/wk;
PEG-INF α 1.5 ug/kg/wk
+ RBV (600-1200 mg/d)
for 12 months
10/16 complete clinical
response; CGs and RNA
HCV undetectable in
responders
Bruchfeld   N=7
HCV-related renal
manifestations
(2/7 MC-related)
IFN α + low-dose ribavirin
(200-600 mg)
or PEG-INF α + low-dose
ribavirin
Improvement of GRF and
proteinuria in 4/7 patients
and sustained viral
response in 5/7.
Roccatello   N=6
MC systematic
manifestations
predominantly renal
(5/6)
Rituximab 375
mg/m
2
/4x/wk
+ rituximab 375 mg/m
2
1 month and 2 months
later
Decrease of cryocrit and
proteinuria at months 2,
6, 12.
Koskinas   N=4
MC patients with
severe sensory-motor
polyneuropathy
INF α-2b 1.5ug/kg/wk +
ribavirin 10.6 mg/kg/d for
48 weeks
Significant improvement
of neurological
parameters in 4/4;
undetectable HCV RNA
and lower CG levels in
3/4 at the end of therapy.
Treatment of HCV-infected patients with high-grade NHL should be based on
cytostatic chemotherapy. 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 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).
Extrahepatic Manifestations of Chronic HCV  281
Further hematological manifestations
HCV-associated thrombocytopenia
Thrombocytopenic conditions (platelet counts below 150 x 10
3
/uL) are often
observed in patients with chronic hepatitis C and result mainly from advanced liver
fibrosis and manifest cirrhosis (Wang 2004). Lack of hepatic-derived
thrombopoietin can inter alia be recognized 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 hypothesized (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 respectively is limited by an increased risk of fibrosis
progression or a substantial elevation of virus. A new orally active thrombopoietin
receptor agonist, eltrombopag, may be used in thrombocytopenic HCV patients in
the future. Its efficacy was recently documented in patients with HCV-related ITP
(Bussel 2007) as well as in HCV-positive patients suffering from thrombocytopenia
due to cirrhosis (McHutchison 2007). However 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). In case of refractory disease or aggravation during the course of
antiviral therapy, rituximab should be considered (Weitz 2005).
HCV-related autoimmune hemolytic anemia
Interpretation of autoimmune hemolytic anemia (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 recognized 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). In this
light, there is, for the time being, little evidence for regarding AHA as a possible
EHM of chronic HCV infection.