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Clin Liver Dis 12 (2008) 611636

Extrahepatic Manifestations
of Hepatitis C Virus Infection
Anna Linda Zignego, MD, PhDa,*,
Antonio Crax` , MDb
a

Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department


of Internal Medicine, University of Florence, Viale GB Morgagni 85, 50134 Firenze, Italy
b
Gastroenterologia and Epatologia, Di.Bi.M.I.S., University of Palermo, Piazza Marina,
3490133 Palermo, Italy

Hepatitis C virus (HCV) is at the same time a hepatotropic and a lymphotropic virus and may cause hepatic and extrahepatic diseases. Extrahepatic
manifestations linked to HCV range from disorders for which a signicant
association with viral infection is supported by epidemiologic data and by
biological plausibility, to anecdotal observations without clear proof of causality. B cell lymphoproliferative disorders (ie, mixed cryoglobulinemia and
non-Hodgkins lymphoma) are the extrahepatic conditions most closely
linked to HCV, having been investigated extensively, and represent a model
for both pathogenetic and clinicotherapeutic deductions. An association
between HCV infection and other morbid conditions, including dermatologic, nephrological, neurologic, endocrinologic, cardiocirculatory, and
lung disorders also has been suggested. Overlap syndromes characterized
by the presence in one patient of manifestations belonging to various pathologic conditionsdtypically of autoimmune/lymphoproliferative natured
would suggest that chronic HCV infection is a distinct systemic disease
with a varying spectrum of clinical manifestations. Interferon-based antiviral therapy is considered, when feasible, the mainstay of treatment for most
HCV-linked extrahepatic diseases. Although its ecacy in curtailing a nonhepatic manifestation after obtaining viral clearance often is seen as a conrmation of the key pathogenetic role played by HCV, clinical symptoms and
viral persistence also may be disjointed, the former persisting even beyond
a sustained viral response to therapy. Because of this fact and the intrinsic
potential inecacy of interferon, which in some cases may even exacerbate

* Corresponding author.
E-mail address: a.zignego@dmi.unifi.it (A.L. Zignego).
1089-3261/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.cld.2008.03.012
liver.theclinics.com

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ZIGNEGO & CRAXI`

extrahepatic conditions, an individualized tailoring of therapy is needed in


these patients.

Classication of extrahepatic manifestations of hepatitis C virus


Extrahepatic manifestations of HCV infection (EHMs-HCV) range from
disorders for which a signicant association with HCV infection is supported clearly by multiple lines of evidence to anecdotal observations without clear proof of causality [1,2]. A tentative classication of EHMs-HCV is
suggested in Box 1. According to such classication, extrahepatic manifestations of HCV infection are distinguished, taking into account the robustness
of available scientic data. It is thus likely that the nosography of some
EHMs-HCV may change over time.
Group A includes EHMs-HCV characterized by a strong association
proven by both epidemiologic and pathogenetic evidence. This category includes B-cell lymphoproliferative disorders (LPDs). Group B includes disorders for which a signicant association with HCV infection is supported by
substantial epidemiologic data and groups C and D associations still require
conrmation and/or a more detailed characterization as opposed to observations that are of similar pathologic nature but of dierent etiology, or idiopathic in nature, or only anecdotal (see Box 1).

Hepatitis C virus-related lymphoproliferative disorders


Mixed cryoglobulinemia
Mixed cryoglobulinemia (MC) is a systemic vasculitis caused by deposition of circulating immune complexes in the small vessels and characterized
by multiple organ involvement, mainly skin, peripheral nerves, kidney, and
salivary glands, and less frequently associated with widespread vasculitis
and malignant lymphoma [36]. The strong association between HCV and
MC has been conrmed repeatedly by serologic and molecular investigations [4,6,7]. Generally speaking, cryoglobulinemias are conditions characterized by the presence of serum immunoglobulins that become insoluble
below 37 C and can dissolve by warming serum (cryoglobulins, CGs). According to Brouet and colleagues [8], CGs are classied on the basis of their
immunoglobulin composition. In type I, they are composed of a pure monoclonal component and usually associated with an indolent B-cell lymphoma,
and in types II and III mixed CGs, they are composed of a mixture of polyclonal IgG and monoclonal IgM or polyclonal IgG and polyclonal IgM, respectively. In MC, the IgM represents an autoantibody bearing rheumatoid
factor (RF) activity. In type II MC (MC II), the IgM RF molecules most
frequently display the WA cross-reactive idiotype [9]. MC II accounts for
50% to 60%, and type III (MC III) for the remaining 40% to 50% of MC.

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Box 1. Classification of extrahepatic manifestations of hepatitis


C virus infection
Association defined on the basis of high prevalence
and pathogenesis
Mixed cryoglobulinemia (complete or incomplete clinical
syndrome)
B-cell non-Hodgkins lymphoma
Association defined on the basis of higher prevalences
than in controls
Monoclonal gammopathies
Porphyria cutanea tarda
Lichen planus
Diabetes mellitus
Associations to be confirmed/characterized
Autoimmune thyroiditis
Thyroid cancer
Sicca syndrome
Alveolitislung fibrosis
Noncryoglobulinemic nephropathies
Erectile dysfunctions
Carotid Atherosclerosis
Psychopathological disorders
Anecdotal observations
Psoriasis
Peripheral/central neuropathies
Chronic polyarthritis
Rheumatoid arthritis
Polyarthritis nodosa
Bechets syndrome
Myositis/dermatomyositis
Fibromyalgia
Chronic urticaria
Chronic pruritus
Kaposis pseudosarcoma
Vitiligo
Cardiomyopathies
Mooren corneal ulcer
Necrolytic acral erythema

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The prevalence of chronic HCV infection in patients who have CGs in


their serum ranges from 19% to more than 50% according to various studies [10,11]. CGs, however, are generally present at low levels, and symptoms
are generally absent or mild in chronically HCV-infected patients, whereas
clinically overt MC syndrome (MCS) would be evident in 10% to 30% of
MC subjects [1012].
Serum mixed CGs, high RF values, and reduced C4 values are the most
frequent laboratory data. The most common symptoms of MCS are weakness, arthralgias, and purpura (Meltzer and Franklin triad). Raynauds phenomenondmicrocirculatory changes of the small vessels of the hands and
feet, identied as color changes in response to colddperipheral neuropathy,
sicca syndrome, renal involvement, lung disorders, fever, and cytopenias
also may be observed [3]. In a recent study involving 231 Italian MC patients, peripheral neuropathy was observed in most cases, representing the
most frequent clinical feature after the triad, followed by sicca syndrome,
Raynaud phenomenon, and renal involvement [13].
MC-related peripheral neuropathy typically includes mixed neuropathies,
which are more often sensitive and axonal. They can manifest themselves as
symmetric distal neuropathies, multiple mononeuritis, or mononeuropathies. Involvement of the central nervous system is unusual and generally
presents as transient dysarthria and hemiplegia. Pathologic ndings show
axonal damage with epineural vasculitic inltrates and endoneural
microangiopathy.
A sicca syndrome (xerostomia and xerophthalmia) caused by involvement of salivary and lacrimal glands is recognized in a large proportion
of MC patients [1418]. This syndrome close resembles primary Sjogrens
syndrome; however it typically lacks antinuclear autoantibodies and antiepithelial neutrophil-activating peptide (ENA, SSA/Ro, SSB/La) [13]. The
pathogenetic role of HCV infection in sicca syndrome and the characteristics distinguishing classic Sjogrens syndrome from those associated with
HCV remain at issue [19]. It has been proposed that HCV infection is a criterion to exclude diagnosis of primary Sjogrens syndrome, especially if mixed
cryoglobulins and hypocomplementemia are present, and anti-SSA/Ro
antibodies are absent [20].
Signicant renal involvement is present in up to one third of patients
who have MC, being observed in about 20% of patients upon clinical presentation of MC and in 35% to 60% of patients over long-term follow-up
[13,21]. The most common features at diagnosis are one or more subclinical features of renal involvement including microscopic hematuria, proteinuria below the nephrotic range (!3 g/24 h), and with normal or
only fairly reduced renal function (creatinine !1.5 mg%). Arterial hypertension is observed in up to 80% of cases [22]. In about 20% of patients,
proteinuria is in the nephrotic range, and in them a nephrotic syndrome
may represent the principal manifestation of MC. About 20% to 30%
of cases present with an acute nephritic syndrome as their rst renal

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615

manifestation [4,23]. Presence of a signicant renal involvement is among


the worst prognostic indices in patients who have MC, even when its
course is variable [13,23]. In a study of 231 patients who had MC, glomerulonephritis with subsequent renal failure was the main complication
(33%), leading to death during long-term follow-up [13]. The typical histologic pattern of renal damage observed in patients who have MC type I
is membranoproliferative glomerulonephritis (MPGN) [13]. The presence
of capillary thrombi, made up of precipitated cryoglobulins and deposits
of IgM in capillary loops typically dierentiates the cryoglobulinemic
form from idiopathic MPGN. In a minority of cases (generally type III
MC), dierent pathologic ndings have been described (ie, focal and mesangioproliferative glomerulonephritis and membranous glomerulonephritis) [24,25].
The association between MC and severe liver damage has been discussed
widely [1,2,9,2629]. Several studies have shown an epidemiologic association between MC and severe liver damage [10,30]. An association between
MC and liver steatosis also has been suggested [31]. Overall, it seems that
both MC and the stage of liver damage are more related to a long duration
of infection.
The occurrence of MC generally has an important impact on the quality
of life and survival of patients who have MC. Survival analysis according to
the Kaplan-Meier method shows a cumulative 10-year survival, calculated
from time of diagnosis, to be signicantly lower in patients who have MC
as compared with an age- and sex-matched general population. Lowest survival rates were observed in males and in subjects who had renal involvement, the main causes of death being nephropathy (33%), malignancies
(23%), liver failure (13%), and diuse vasculitis (13%) [13].
Because of its variable presentation, no standardized criteria for the diagnosis and staging of MCS are available, even if classications have been proposed [32]. In the presence of purpura, mixed CGs, reduced C4 values, and
organ involvement, the diagnosis of MCS is relatively easy. Quite frequently, however, it is suggested by abnormal laboratory data (RF test or
mixed CGs or reduced C4 values) with or without mild symptoms like arthralgias or asthenia. Moreover, some subjects who have HCV may show
clinically evident MCS, though incomplete from a serologic point of view,
mainly with the temporary absence of circulating CGs. This may be explained by the diculty in a proper determination of the presence of
CGs, because of their thermolability and the variability of the rate of
CGs responsible for vasculitic damage [13,33].
Because some mixed CGs are present in low concentrations, the dierentiation between type II and type III CGs often requires a more sensitive
method for immunochemical characterization such as electroimmunoxation or Western blot, than conventional immunoelectrophoresis [34]. Several
data, including the presence of a clonal expansion of B-lymphocytes (BL) in
peripheral blood or liver inltrates [3538], and the histopathological

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features of the bone marrow and liver lymphoid inltrates, conrm the lymphoproliferative nature of MC. Some studies have shown that:
B-cell clonal expansion (in particular of RF B-cells) underlies MC.
This condition is associated with Bcl2/JH rearrangement.
MC II can evolve into a frank b-cell non-Hodgkins lymphoma (NHL) in
approximately 8% to 10% of cases after a long period of time [13].
From a histopathological point of view, the presence of monoclonal lymphoproliferation of uncertain signicance (MLDUS) in subjects who have
clinicolaboratory features of MC II is typical [33,3941]. MLDUS represents oligoclonal proliferations of small BL, preferentially located in the
bone marrow and liver. In these organs, MLDUS is generally present
with phenotypic and histologic aspects comparable to indolent B-cell lymphoma. Further immunemorphologic analysis reveals two dierent varieties: the rst and more frequent variety, with analogous features to B-cell
chronic lymphatic leukemia (CLL)/small cell lymphoma and a second, less
frequent, lymphoplasmacytic-like form. The prevalence of these histologic
patterns has varied in dierent reports [40,4248].
Lymphoma
HCV-associated lymphoid malignancies can be observed during the
course of MC or as non-MC related idiopathic forms. About 8% to 10%
of MC II evolves into a frank lymphoma [43,49], generally after long-lasting
infection. According to recent data, MC patients had a 35 times higher risk
of NHL than the general population [50].
An association between B-cell derived NHL and HCV infection initially
was suggested by studies performed in populations from southern Europe
and the southern United States, [46,5155], whereas some northern European and northern United States or Canadian surveys did not conrm
a higher prevalence of chronic HCV infection in patients with lymphoma
than in the general population [5661]. During the last decade, many studies
performed at dierent latitudesdgenerally larger in size than initial onesd
as well as meta-analysis, were able to conrm the existence of such association, even with a clear south/north gradient of prevalence. These dierences
at least partly reect how HCV is diuse at dierent rates in the specic
populations studied, but also suggest a likely contribution of environmental
or genetic factors [62] to lymphomagenesis.
Although virtually all types of lymphoid malignancy can be found in patients with HCV infection, the strongest association is with B-cell derived
NHL [18,40,51,53,54,6365]. The use of dierent classications presented
in the various studies, however, may confound the evaluation of the actual
incidences of each histotype [48,6567]. Peripheral B-cell derived indolent
NHL appears to be the most frequent HCV-associated lymphoma in
many studies. According to the Revised European-American Lymphoma

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617

(REAL) classication/World Health Organization (WHO) Classication


[68,69], the main HCV-related histotypes include B-cell chronic lymphocytic
leukemia/small lymphocyte lymphoma, diuse large B-cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma [40]. A recent European multicenter survey suggests a specic role
of HCV infection in the pathogenesis of diuse large B-cell lymphoma
[70]. Among marginal zone lymphomas, a special association with HCV infection was reported for the mucosa-associated lymphoid tissue (MALT)
lymphoma [65,71,72] and the splenic forms. This is conrmed by reports
of regression of marginal splenic lymphoma after successful HCV clearance
because of antiviral therapy, in spite of previous ineective chemotherapy
[7375]. In general, the observations of a hematological regression of
some HCV-associated NHL and expanded B-cell clones following eective
antiviral therapy represent a consistent argument in favor of the pathogenetic role played by HCV infection, even if a direct antineoplastic role of interferon cannot be excluded.
A serum monoclonal gammopathy, more frequently type IgM/K, has
been described among HCV-associated LPDs [76]. In most patients with
HCV, however, MG was classied as MGUS (monoclonal gammopathies
of uncertain signicance), whereas a few patients who have HCV with
monoclonal gammopathy can be considered as aected by myeloma according to their clinicopathologic characteristics [69,77,78].
Pathogenesis of hepatitis C virus-related lymphoproliferative disorders
It now is accepted widely that the pathogenesis of LPDs is a complex,
multistep process. Several studies investigating the pathogenetic mechanisms involved in the evolution of HCV infection to B-cell LPDs are available, but in spite of interesting hypotheses, the exact mechanisms involved
are not known. Originally, the observation of HCV lymphotropism at the
beginning of the 1990s led to the hypothesis of a causal link between infection of lymphatic cells and autoimmunelymphoproliferative disorders [79].
Earlier, it was observed that both HCV-positive strand (genomic) and -negative strand (antigenomic replicative intermediates) could be detected in
peripheral blood mononuclear cells (PBMC) taken from patients who had
chronic HCV infection [80]. During the past decade, ex vivo and in vitro
studies with techniques of increasing specicity and sensitivity have led to
better characterization of HCV lymphotropism [8187]. Nonetheless, no
clear proof of a direct link between HCV lymphotropism and LPD pathogenesis has been obtained, despite the demonstration of a more extensive involvement of the lymphatic system by HCV infection in patients who have
B-cell LPDs than those who do not [5,88,89], and of an enhancing eect of
B-cell infection by HCV in promoting the proliferation of lymphoid cells
[90]. By contrast, several studies have supported an indirect role of HCV
through activation of the hosts immune response [37,9194]. The

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importance of a sustained antigenic stimulation by viral epitopes and of the


specic binding between the HCV E2 protein and the CD81 molecule has
been stressed [95], supporting the key role played by the promotion of
a strong polyclonal B-cell response to chronic viral infection that progressively would favor lymphomagenesis until nal malignant transformation.
Contrasting data, showing the possibility that HCV may favor mutations
of immunoglobulin genes and oncogenes by a hit and run mechanism, were
obtained in cell lines and in cultured cells taken from patients with HCV [96].
This analysis originated from previous observations showing a signicant association between Bcl-2 rearrangement (14;18 translocation) and chronic
HCV infection, especially in those subjects who developed type 2 MC [97
102], and MALT lymphoma [103]. In patients who had type II MC, the analysis of synchronous and metachronous blood samples showed the clonal
expansion of B-cells harboring this chromosomal rearrangement [99]. In
addition, it was possible to demonstrate an overexpression of the antiapoptotic Bcl-2 protein with a higher bcl-2/bax ratio in t (14;18)-positive B-cell
samples [99], and a modication of t (14;18) B-cell clone detection following
antiviral treatment [104]. Only treatments leading to sustained clearance of
HCV RNA from serum led to the regression of clones, with consequent
lack of t (14;18)-positive cells in PBMC at the end of treatment, whereas
this eect was not observed in nonresponder patients [104]. An extensive follow-up of HCV-positive MC patients after sustained virological response to
IFN-based treatments has revealed the possibility of viral persistence in the
lymphatic compartment in the absence of serum HCV RNA or liver infection.
Interestingly, isolated lymphatic infection was associated strictly with the persistence of both MC-syndrome and t (14;18)-bearing B-cell clones.
These observations rearm, after more than a decade since the original
suggestions, the strong likelihood of a role played by HCV lymphotropism
in lymphomagenesis, but the exact mechanisms involved remain unclear. On
the other hand, they strongly suggest that the pathogenesis of MC is not
necessarily related to the intrahepatic challenge between HCV epitopes
and lymphoid inltrates. Considering the complexity of LPDs and the heterogeneity of HCV-associated LPDs, it is conceivable that MC and other
HCV-related LPDs may have dierent pathogenetic pathways. An accurate
understanding of these dierent pathways and the frequency of their involvement in the pathogenetic mechanisms would be essential for the correct
appraisal of both therapeutic and preventive measures [105,106]. An attempt
to summarize current knowledge of the interrelations between HCV and
LPDs is presented in Fig. 1.
Treatment of hepatitis C virus-related mixed cryoglobulinemia
and lymphoproliferative disorders
Before the identication of its viral etiology, MC treatment included
a variable combination of anti-inammatory and immunosuppressive

619

EXTRAHEPATIC MANIFESTATIONS OF HEPATITIS C VIRUS

+
HCV

HCV-induced mutagenesis

t(14;18)/others?
Bcl-2 overexpression
B-cell apoptosis
inhibition

Sustained Bcell activation

Genetic and/ or
environmental factors

Prolonged BL
survival

MC

Likelihood of reversion after HCV eradication

HCV E2 /CD81
binding
B-cell infection

Additional genetic aberrations

Malignant NHL

Fig. 1. Pathogenesis of hepatitis C virus-related lymphoproliferative disorders: an evidencebased hypothesis.

strategies. Soon after linking chronic HCV infection to MC, several studies
were carried out to assess the eect of interferon (Table 1). Interferon monotherapy initially was used, sometimes in association with corticosteroids
(CS) [24,26,107116], and resulted generally in eective improvement in
MCS, even if associated with a very high relapse rate after discontinuation
of therapy (see Table 1). In later studies, the combination of interferon with
ribavirin (RBV) oered better results than interferon monotherapy [117
120]. Further improvement in the sustained virological response (SVR)
rate was obtained by the introduction of pegylated interferons (IFNs)
[121123] (see Table 1). Additional controlled studies, however, are needed
to gain denitive information.
Interestingly, all available studies show that clinicoimmunologic and virologic responses generally are related [112,117,119,122124]. The persistence of isolated lymphatic infection after therapy was associated with
persistence of MC syndrome stigmata [105]. Disappearance of BL monoclonal inltrate from bone marrow and BL expansion in peripheral blood following IFN therapy also has been shown. In particular, the antiviral
response was proven to be signicantly associated with the absence of circulating B-cell clones bearing t (14;18) translocation [99,104,125]. The

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Table 1
Antiviral therapy in hepatitis C virus-related mixed cryoglobulinemia
Year

Number
of patients

Ferri

1993

15

Ferri

1993

26

Marcellin
Johnson
Misiani

1993
1993
1994

2
4
27

Dammacco

1994

15
16

Johnson
Mazzaro
Mazzaro

1994
1994
1995

Casaril
Cohen
Akriviadis
Casato

1996
1996
1997
1997

14
18
18
18
25
20
20
31

Durand
Calleja

1998
1999

5 NR
18
8 NR

Zuckerman

2000

9 NR

Treatment
Interferon 2 MIU/d (1 m)2 MIU
three times weekly (5 m) (CS)
Interferon 2 MIU /d (1 m)2 MIU
three times weekly (5 m) (CS)
Interferon 3 MIU three times weekly
Interferon 110 MIU
Interferon 1.5 MIU three times weekly
(1 w)3 MIU three times weekly
(23 w)
Interferon 3 MIU three times weekly
Interferon 3 MIU three times weekly
(CS)
Variable interferon
Interferon 3 MIU three times weekly
Interferon 3 MIU three times weekly
Interferon 3 MIU three times weekly
Interferon 6 MIU three times weekly
Interferon 3 MIU three times weekly
Interferon 35 MIU three times weekly
Interferon 3 MIU/d (3 m)3 MIU
three times weekly (R9 m)
RBV
Interferon 3 MIU three times weekly
Interferon 3 MIU three times weekly
RBV
Interferon 3 MIU three times weekly
RBV

Treatment
duration (months)

End of
treatment

Response
sustained

80%

100%

6
212
6

50%
75%a
60%

12
12

53.3%
52.9%

25%
33.3%

612
R12

0a
28%
28%
39%
52%b
60%c
65%b
62%

1036
12
12

100%
55%
63%

6
12
6

78%

11%
22%
9%c
33%b

0%
28%
38%

ZIGNEGO & CRAXI`

Author

2002

14

Mazzaro

2003

27 NR or Rel

Alric

2004

18

Cacoub

2005

Saadoun

2006

32
40

Variable interferon RBV


( variable CS)
Interferon 3 MIU three times weekly
RBV
Interferon 3 MIU three times weekly
or pegylated interferon RBV
Pegylated interferon 1.5 mg/kg/w
RBV
Interferon 3 MIU three times weekly
RBV
Pegylated interferon RBV

656
12

71%
85%

R18

70%

R10

88%

R6

67.5%
56.3%

Kidney function improvement.


Cryoglobulins disappearance.
c
Both complete and partial mixed cryoglobulinemia syndrome response.
Abbreviations: CS, corticosteroids; d, daily; MIU, millions of international units; m, months; NR, nonresponders; RBV, ribavirin; Rel, relapsers; w, week.
Data from: Zignego AL, Giannini C, Ferri C. Hepatitis C virus-related lymphoproliferative disorders: an overview. World J Gastroenterol 2007;13:246778.
b

EXTRAHEPATIC MANIFESTATIONS OF HEPATITIS C VIRUS

Cacoub

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reappearance of circulating translocated BL clones after virological relapse


at the end of treatment, and their persistent detection in subjects with unmodied viral load after antiviral therapy, strongly indicates that clonal expansion of translocated cells depends on modications of viral replication
induced by antiviral treatment [104,125]. More recently, long-term analysis
of patients with HCVand MCS showing SVR after therapy indicated that
occult lymphatic infection and persistence of MCS stigmata also were associated with persistent determination of expanded t (14;18) carrying B-cell
clones [105]. These data suggest the critical role played by a complete viral
eradication and its possible role in preventing the evolution of LPD.
An algorithmic approach to the treatment of HCV-related MCS is outlined in Fig. 2. Overall, available data show that combination antiviral treatment with pegylated interferon and RBV should be considered as the rst
option in subjects who have HCV-positive MCS. Interferon-based antiviral
treatment in HCV patients who have MCS is usually more complex to handle than in patients without MC for several reasons, including: the absence
of standardized treatment protocols, the frequent presence of contraindications, and the diculties in the accurate interpretation of results. Biochemical markers of MC response (cryocrit, RF, or complement values) may be
related less strictly to virological response than alanine aminotransferase
(ALT) levels. This may conrm the importance of a multistage pathogenetic

Assessment of MCS and of contraindications to IFN-based therapy


Contraindications to IFN
and/or severe MCS

No contraindications
and mild/moderate MCS

Moderate-severe MPGN, skin vasculitis


or
Severe-rapidly progressive MPGN
Severe sensomotor neuropathies
Widespread vasculitis

Mild-moderate
purpura Weakness
Arthralgias
Mild neuropathy

PEG IFN
plus ribavirin*
Rituximab
LAC diet
Low-medium doses
CS +/- other sympto matic
treatment

SR

NR

PE + CS +/-CF
se
ve
re

NON
RESPONDERS

RESPONDERS

Antiviral
therapy ?

Fig. 2. An algorithmic approach to the treatment of hepatitis C virus-positive mixed cryoglobulinemia (MC). *Schedule as for non-MC patients. Abbreviations: CS, corticosteroids; CF, cyclophosphamide; NR, no MCs response; PE-plasma exchange; SR, sustained MCs response.

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mechanism in MCS, suggesting the need for precise monitoring of this category of patients and the denition of predictive markers.
For patients in whom antiviral treatment is contraindicated or is not
tolerated or in patients who are nonresponders, alternative therapeutic
approaches should be used, CS, immunosuppressive drugs, Non-Steroidal
Anti-Inammatory Drugs (NSAIDs), plasmapheresis (PE) and a hypoantigenic diet (low antigen content [LAC] diet) administration [41,126]. Treatment should be tailored to the individual patient according to the severity
of clinical symptoms, also considering the possible additional factors involved (age, renal failure, comorbidities), and the time (weeks or months)
required for symptom remission. Corticosteroids represent the most commonly used nonantiviral therapy for MCS and generally allow the control
of most MC symptoms even at low doses. They may favor HCV replication, however, induce several adverse eects, and do not signicantly modify the natural history of the disease. Cytostaticimmunosuppressive drugs
(ie, cyclophosphamide, chlorambucil, and azathioprine)may be used, especially during the acute phases of MCS, but they may cause severe adverse
eects [127]. A special note must be made of new B-cell specic immunosuppressive therapy based on the use of chimeric antibodies (rituximab)
against the CD20, a B-cell specic surface antigen [128,129]. Rituximab is
eective in most patients who have MC, leading to marked improvement
or resolution of the syndrome, especially of skin lesions, and to regression
of the expanded B-cell clones [128,129]. This therapeutic approach appears
to be very promising for managing patients who have MCS, but future controlled studies still are required to establish its ultimate role in treating
HCV-related MCS. It should be stressed that rituximab, as an immunosuppressive agent, leads to an increase in HCV replication, but no signicant
reactivation of HCV-related liver disease has been reported. Its use in combination with direct antiviral molecules [41,128131], when available, probably will lead to further improvement in management.
Other therapeutic measures include plasma exchange (PE) and LAC diets.
PE (ie, the apheretic removal of circulating immunocomplexes) specically is
indicated in the presence of clinically signicant acute manifestations (cryoglobulinemic nephritis, severe sensorimotor neuropathies, cutaneous ulcers,
and hyperviscosity syndrome). The LAC diets, generally prescribed at the initial stage of MCS, essentially act by reducing the antigen load to the reticulo
endothelial system, thus allowing a more ecient removal of CGs.
Recent studies, performed in specic subgroups of patients with HCVassociated NHLs, such as marginal zone lymphomas [73,132], support the
rationale for the use of antiviral therapy also in the setting of malignant
HCV-associated LPDs. In the study by Hermine and colleagues [73],
a complete remission of Splenic Lymphoma with Villous Lymphocytes
(SLVL) was observed in most HCV-positive patients but in none of
HCV-negative cases following treatment with IFN. In addition, regression
of clonal proliferation in response to antiviral treatment was shown to be

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associated clearly with virological response [99,104,125]. Seemingly only


a proportion of HCV-associated lymphomas are cured with antiviral therapy. Also in responsive patients who had SLVL, the rearrangement of the
monoclonal immunoglobulin genes persistently was detected in the blood
even after a complete hematological response [75]. Such data suggest
that the multistep lymphomagenetic cascade may have points of no-return,
making the LPD progressively independent from HCV infection (see
Fig. 1). Although antiviral therapy appears to be an attractive therapeutic
tool for low-grade HCV-positive NHL, in intermediate and high-grade
NHL, chemotherapy is most likely to be necessary while antiviral treatment possibly could represent a maintenance therapy [133]. Further studies
are needed to standardize antiviral therapy better in HCV-associated
NHL. The use of rituximab in HCV-associated NHL, in monotherapy
or in combination with antiviral treatment and/or chemotherapy, appears
very promising, particularly in the setting of low-grade NHL, where rituximab monotherapy has been proposed as rst-line treatment [134136]. In
spite of the limited number of described cases, rituximab may be considered a safe and eective therapy for HCV-related indolent B-cell
lymphoma.

Other extrahepatic disorders and overlap syndromes


Many and dierent disorders have been linked to HCV infection. In most
cases, because of possible methodological bias, mainly in patient selection in
the various studies, it is dicult to verify whether the suggested association
is coincidental or whether a real pathogenetic link exists. Several conditions
are observed more frequently in the context of an MC and quite rarely as
idiopathic forms. This is the case of skin, kidney, salivary glands, or lung
disorders. In addition, a clinicoserological overlap between dierent
EHMs-HCV often is observed [32,137,138]. In spite of the heterogeneity
of the morbid conditions that have been linked to HCV, two issues are quite
constant: the pathogenetic involvement of the hosts immune system and the
symptom severity with consequent worsening of quality of life [139]. In addition, extrahepatic manifestations may be observed variably in the presence
or absence of hepatic damage. On the whole, these observations support the
view of HCV infection as a distinct systemic disease with widely variable
clinical expressions.
Dermatopathologic manifestations
In addition to MC-related purpura, HCV infection also has been associated with several cutaneous disorders, including the sporadic variant of porphyria cutanea tarda (PCT) [1,140143], a metabolic disorder characterized
by reduced hepatic activity of uroporphyrinogen decarboxylase, and with
oral lichen planus (OLP) [144154]. A strong association between the

EXTRAHEPATIC MANIFESTATIONS OF HEPATITIS C VIRUS

625

sporadic form of PCT and HCV was suggested by the high prevalence
(greater than 50%) of HCV markers in these patients, mainly in studies
from southern Europe [1,140143]. In HCV-positive patients without
PCT, however, no signicant alteration in porphyrin metabolism was shown
[142,155,156]. Epidemiologic studies also proved the existence of a correlation between OLP and chronic HCV infection [144]. The prevalence of HCV
infection in a large population of patients who had OLP was about 27%
[145]. Data supporting this correlation essentially stem from studies performed in Japan [144] and southern Europe [145148], but these were not
conrmed in other populations [149152]. It generally is agreed that in these
cutaneous disorders, HCV infection plays an indirect role, probably acting
as a triggering factor in genetically predisposed individuals. As a matter of
fact, attempts to cure these disorders with antiviral therapy led to discordant, but generally negative results with the possible induction of a clinical
manifestation in previously unaected patients or worsening of the disease
[33].
Nephrological disorders
A causative association between HCV and non-MC related forms of renal damage (membranoproliferative glomerulonephritis without simultaneous presence of cryoglobulins, or membranous nephropathy) has been
suggested, but requires conrmation [33].
Neurologic disorders
Neurologic complications have been associated with HCV infection
mostly in the context of MC, but also in the absence of this condition
[157,158]. Only cryoglobulinemic neuropathy, however, has been associated
clearly with HCV infection.
Disorders of the joints, bones and muscles
HCV-related chronic polyarthritis can be observed in HCV-positive patients both with and without MC [13,159]. True rheumatoid arthritis
(RA), in keeping with classic criteria, seems to be uncommon in subjects
who have HCV. In patients who have HCV, tests are usually negative for
antibodies to cyclic citrullinated peptides (anti-CCP), which may help to differentiate the two conditions (true RA and HCV-related RA-like form). By
contrast, intermittent oligoarthritis, generally not erosive and involving the
big and middle-sized joints, is observed frequently [13,32,159]. An association of HCV infection with osteosclerosis and a correlation between such
manifestation and the imbalance in the osteoprotegerin/RANKL (Receptor
Activator of NF-kB Ligand) system with a predominance of osteoprotegerin
also were observed in some studies [160,161]. HCV infection also was suggested to be associated with myositis and dermatomyositis [162].

626

ZIGNEGO & CRAXI`

Endocrinologic disorders
Practically all known manifestations of a thyroid disorder have been described in patients who have HCV infection, but frequently with discordant
data [163167]. Geographic, genetic, or environmental cofactors [168171]
and dierent methodological approaches partially explain discordant observations. The most frequently observed HCV-associated thyroid disorder involves circulating antithyroid peroxidase antibodies in female subjects [166].
Subclinical hypothyroidism was observed in 2% to 9% of patients who had
chronic HCV infection and particularly in those who had MC [2,165,172].
Finally, a higher prevalence of papillary thyroid carcinoma in patients
who had HCV was observed [173175]. Interferon alfa therapy may exacerbate or induce underlying latent thyroid disorders, and the relative contribution of the role played by HCV or by antiviral therapy in leading to such
associations has been discussed [166,176178]. Recently, it was suggested
that molecular mimicry between viral and self-antigens might be involved
in the pathogenesis of HCV-associated autoimmune thyroid diseases [179].
A high prevalence of diabetes mellitus type 2 was observed in patients
who had chronic HCV infection in several studies [180187], and it has
been suggested that HCV acts as a risk factor independently of liver disease
[188]. In patients who had HCV infection, the appearance of diabetes type 2
was associated with insulin resistance and was considered part of a complex
virus-induced metabolic syndrome including both hepatic (steatosis) and extrahepatic manifestations. In agreement with this, an association between
carotid atherosclerosis and HCV infection recently has been suggested
[189,190].
Lung and cardiocirculatory disorders
A pathogenetic link between HCV infection and idiopathic pulmonary brosis has been reported [191,192]. The fact that MC can be complicated by
an involvement of pulmonary interstitium suggests that such association in
some cases can be related to a pre-existing MC [193]. An association between HCV and hypertrophic cardiomyopathy was suggested by the observation of signicantly higher prevalence of anti-HCV in Japanese patients
with such condition compared with controls [194]. Studies performed in
Italy and in Greece by other authors, however, did not conrm this association. Regardless, the recent determination of a signicantly higher prevalence of carotid atherosclerosis in patients with HCV infection [189] is
noteworthy; this association was mostly evident in case of active viral replication [190]. In a very recent study, the association between HCV chronic
infection and carotid atherosclerotic lesions was conrmed also in a large
Italian population. Further, HCV RNA sequence was determined in carotid
plaques, strongly suggesting a local proatherogenetic action of the virus inside the plaque [195].

EXTRAHEPATIC MANIFESTATIONS OF HEPATITIS C VIRUS

627

Psychopathological disorders
Patients who have HCV infection have a low quality of life and may experience excessive fatigue, decreased cognitive ability, and low mood tone
[196198]. These symptoms are not related directly to liver damage, and it
has been proposed that the virus may cause direct cerebral dysfunction by
an unknown mechanism [197]. Recently, plasma tryptophan and kynurenine
content in blood, together with indoleamine 2,3-dioxygenase activity in
macrophages, was evaluated in a cohort of patients who had mild HCV-related chronic liver disease. Patients also underwent psychopathological evaluation. Serum tryptophan concentrations were lower than those of healthy
subjects or patients who had chronic HBV infection, and were associated
with high levels of anxiety and depression, strongly suggesting that these
modications may be causally related. In addition, mechanisms involved
in the pathogenesis of HCV-associated reduced tryptophan levels appeared
dierent from those observed in other chronic infections, thus possibly representing a new model for viral-induced alterations of tryptophan metabolism [199201].

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