Beruflich Dokumente
Kultur Dokumente
Extrahepatic Manifestations
of Hepatitis C Virus Infection
Anna Linda Zignego, MD, PhDa,*,
Antonio Crax` , MDb
a
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
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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
617
618
619
+
HCV
HCV-induced mutagenesis
t(14;18)/others?
Bcl-2 overexpression
B-cell apoptosis
inhibition
Genetic and/ or
environmental factors
Prolonged BL
survival
MC
HCV E2 /CD81
binding
B-cell infection
Malignant NHL
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%
Author
2002
14
Mazzaro
2003
27 NR or Rel
Alric
2004
18
Cacoub
2005
Saadoun
2006
32
40
656
12
71%
85%
R18
70%
R10
88%
R6
67.5%
56.3%
Cacoub
621
622
No contraindications
and mild/moderate MCS
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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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
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].
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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