|
|
Extrahepatic
Manifestations of Hepatitis
C Virus
|
|
|
| |
Richard K. Sterling, MD and
S. Bralow, MD
Richard K. Sterling, MD
Division of
Gastroenterology, Hepatology,
and Nutrition, Virginia
Commonwealth University
Health System, 1200 E. Broad
Street, West Hospital, Room
1492, Richmond, VA 23298,
USA.
Current Gastroenterology
Reports Feb 2006 Vol 8 Issue
1, 8:53-59
ABSTRACT. Given the
high prevalence of chronic
hepatitis C virus (HCV)
infection, its clinical
sequelae account for a
significant proportion of
patients presenting to
gastroenterologists and
hepatologists. Whereas the
hepatic manifestations of
hepatitis C are well
described, including
hepatitis, cirrhosis, and
the development of
hepatocellular carcinoma,
the extrahepatic
manifestations, though
common, are less well
appreciated. Although
nonspecific, fatigue and
arthralgias are very common
in those with chronic
hepatitis C. Extrahepatic
syndromes have been reported
in as much as 36% of HCV
patients, but the exact
prevalence is not known.
Patients with these
syndromes can be divided
into those with a high
degree of association and
those with a more moderate
or mild association with
HCV. The most prevalent
extrahepatic diseases with
the highest degree of
association with HCV are the
essential mixed
cryoglobulins with skin,
neurologic, renal, and
rheumatologic complications.
Non-cryoglobulin diseases
with a less definite
relationship to HCV include
systemic vasculitis, splenic
lymphoma, porphyria cutanea
tarda, and the sicca
syndromes. This article
highlights the
pathophysiology and clinical
manifestations of these
disorders. Treatment of
these extrahepatic
manifestations is directed
at the HCV virus itself as
well as the extrahepatic
organ affected and often
requires a multidisciplinary
approach.
Table 1. Extrahepatic
diseases associated with
hepatitis C virus Strong and
proven association
Mixed cryoglobulinemia (MC)
Purpura: cutaneous
vasculitis
Neuropathy
Arthralgias, non-deforming
Type 1 membranoproliferative
glomerulonephritis (MPGN)
Chronic fevers
Asthenia: fatigue, weakness
Moderate association
Non-cryoglobulinemia
systemic vasculitis (PAN)
Splenic lymphoma
B-cell non-Hodgkin's
lymphoma
Sicca syndrome
Porphyria cutanea tarda
Mild association
Thrombocytopenia
Type 2 diabetes mellitus
Autoimmune thyroiditis
Lichen planus
Introduction
Since 1989, when the
hepatitis C virus (HCV) was
identified and recognized as
the major component of the
so-called non-A, non-B
transfusion hepatitis, the
clinical course of HCV has
been well described. It has
been estimated that nearly
3% of the world's
population, or 170 million
individuals, have been
infected with HCV [ 1**]. In
developed countries the
incidence is lower, but in
endemic areas it may reach
10% to 30% [2]. In the
United States, the overall
prevalence has been
estimated at 1.8% or 3.9
million people, with 2.7
million chronically
infected. In developing
countries, HCV appears to be
related to medical
procedures, vaccinations,
and parenteral drug use.
Since 1989, the incidence of
acute HCV has declined by
about 80% in the United
States due to screening of
blood products, but the
overall prevalence of
chronic HCV has not
decreased significantly. At
least 60% of HCV is now due
to illicit drug use.
The onset of acute HCV is
often difficult to
substantiate because of the
mild or nearly absent
symptoms marking the acute
and chronic phases of this
disease. By dating the time
of the last known exposure
to the virus, one can
estimate the incubation
period, which ranges from 6
to 7 weeks on average but
has been reported to be as
short as 2 weeks and as long
as 26 weeks [2]. Chronic HCV
is said to be present if the
viremia or elevation of
serum alanine
aminotransferase (ALT)
persists longer than 6
months. Once an individual
is exposed, chronic HCV
develops in 60% to 70% of
cases and can progress to
cirrhosis in approximately
20% of infected persons [3].
Hepatic decompensation or
hepatocellular carcinoma may
develop in approximately 20%
of patients with cirrhosis,
and approximately 13% of
these patients die, or
approximately 4% of all
those infected [1**]. Mild
symptoms usually persist for
two to three decades before
complications occur.
Consequently, HCV has been
labeled a "silent epidemic,"
and the natural course is
slow but progressive.
Because of its ability to
activate the immune system
yet avoid elimination,
chronic infection can result
in accumulation of immune
complexes and stimulate
antibodies, which can result
in extrahepatic conditions.
Extrahepatic
Manifestations of Chronic
HCV
Extrahepatic syndromes have
been reported in up to 36%
of HCV patients, but the
exact prevalence is not
known. As many as 36
different syndromes have
been reported to be related
to HCV, but many of these
instances are only case
reports [4*]. These
syndromes can be divided
into those with a high
degree and those with a more
moderate or mild association
with HCV (Table 1). Severe
fatigue is the most common
extrahepatic manifestation
of HCV and frequently
interferes with quality of
life [5*]. Fatigue
associated with liver
disease typically is mild
after adequate sleep and
progresses throughout the
day or after prolonged
activity. In those who have
fatigue from the time they
awaken (so-called morning
fatigue) alternative causes
should be explored, such as
depression or sleep apnea.
Fatigue from chronic HCV
usually decreases with a
sustained virologic response
(SVR) but occasionally
persists.
Arthralgias are also common
in patients with chronic HCV
[6, 7]. Because rheumatoid
factor (RF) is often
positive in patients with
chronic HCV, elevations in
RF require differentiation
from rheumatoid arthritis.
Elevations in RF are also
seen in the majority of
patients with
cryoglobulinemia, and an
elevated RF in the right
clinical circumstance
requires testing for this
condition.
Hepatitis C virus has
lymphocyte tropism, and when
associated with mixed
cryoglobulins, the virus has
a strong affinity to bind
with B lymphocytes via
CD81-producing
autoantibodies, which are
commonly elevated in HCV
[1**, 8]. Autoimmune
hepatitis (AIH) must
therefore be ruled out, but
autoantibody titers are
usually lower in HCV [2].
Furthermore, when compared
with HCV, there is no female
preponderance, no
association with HLA-DR, and
no other clinical
manifestations of AIH in
these patients with
nonspecific elevations in
autoantibodies.
High degree of
association
The most prevalent
extrahepatic diseases with
the highest degree of
association with HCV are the
essential mixed
cryoglobulins, with skin,
neurologic, renal, and
rheumatologic complications
[8]. However, only a small
number of patients with
mixed cryoglobulinemia
develop extrahepatic
manifestations. Non-cryoglobulin
diseases with a less
definite relationship to HCV
include systemic vasculitis,
splenic lymphoma, porphyria
cutanea tarda (PCT), and the
sicca syndromes. The
mechanism by which HCV
promotes many of these
extrahepatic disorders is
still not completely clear.
Cryoglobulin complexes were
first described in 1966 as
the cause for a triad of
symptoms: purpura,
arthralgias, and fatigue
[9]. Cryoglobulins are
immunoglobulins that
precipitate in the cold and
are classified into three
types: type I is composed of
monoclonal immunoglobulins
and usually associated with
malignancies of the immune
system; type II is composed
of polyclonal IgG and
monoclonal IgM; and type III
is composed of polyclonal
IgG and polyclonal IgM [10].
Types II and III are
referred to as mixed
cryoglobulinemia (MC), and
the IgM usually has RF
activity. When no
precipitating factor is
identified, the syndrome is
termed essential MC (EMC).
Until the discovery of HCV,
hepatitis B virus (HBV) was
implicated in MC. However,
since the discovery of HCV,
it has emerged as the major
etiology of EMC [10].
The prevalence of HCV in MC
is estimated at 45% to 90%
[8]. The majority of these
patients are asymptomatic.
Clinically significant
cryoglobulinemia occurs in
only a fraction of those
with chronic HCV. This
discrepancy has not been
fully explained, and there
may be host genetic factors
that predispose patients
with chronic HCV to MC,
including HLA haplotypes B8
and DR3, as well as viral
factors. HCV genotype 2a has
been reported to be more
prevalent in MC, but this
finding has not been
confirmed [11].
Clinically, patients with MC
present with arthralgias,
symmetrical arthritis,
fatigue, vasculitis,
palpable purpura (from a
leukocytoclastic vasculitis)
(Fig. 1), and neuropathy.
Cutaneous leukocytoclastic
vasculitis or palpable
purpura occurs only in the
presence of MC, with a
frequency reported to be as
high as 40% to 95%, which
makes this condition the
most frequent extrahepatic
manifestation [12]. HCV
antigens are found in the
skin lesions and respond to
combination interferon (IFN)
therapy. The purpuric
lesions are most often on
the legs, back, or trunk.
The dermal capillaries
become plugged with
precipitated MC, and
neutrophilic infiltrates
involve the walls of the
small vessels. However,
necrosis seldom occurs. The
skin lesions usually appear
in the winter and are
intermittent, lasting 3 to
10 days and leaving an area
of brownish pigmentation.
Raynaud's phenomenon and
acrocyanosis with digital
ulceration occur in 25% of
patients.
Renal involvement occurs in
up to 50% of patients and
usually presents as
glomerular disease [1**,
13**]. HCV- associated
glomerular diseases include
membranous
glomerulonephritis (MGN),
membranous nephropathy (MN),
and membranoproliferative
glomerulonephritis (MPGN),
with the vast majority of
patients having type I MPGN.
Laboratory testing shows
positive HCV RNA,
proteinuria, microscopic
hematuria, mild to moderate
renal insufficiency,
hypocomplementemia
(especially low C4 with
modest depression of CH50
and C3), and elevated C1q
binding [14]. The
pathogenesis of MGN includes
glomerular deposition of
immune complexes containing
HCV antigens, anti-HCV IgG
antibodies, and IgM RF
(anti-IgG antibodies) [10].
This results in local
complement activation and an
inflammatory infiltrate. HCV
RNA is concentrated over
100-fold relative to serum
in the cryoprecipitate. On
renal biopsy, the
circulating immune complexes
localize to the
subendothelium and mesangium
to initiate local
inflammation [14]. This
results in a proliferative
lesion with thickening of
the capillary membranes.
Immunofluorescence
demonstrates granular
staining of the capillary
walls with IgM, IgG, and C3.
In addition,
tubulointerstitial fibrosis
and vasculitis of the small
and medium arteries can be
seen. In patients with
HCV-associated MN, there is
normal cellularity with
basement membrane
thickening, granular
capillary wall deposits of
IgG and C3 on
immunofluorescence, and
subepithelial immune
deposits seen on electron
microscopy. Occasionally,
patients with chronic HCV
can develop membranous
nephropathy in the absence
of cryoglobulins or evidence
of MC. In these patients, RF
is negative and serum
complement levels are
normal.
Arthralgias frequently occur
in HCV but show no evidence
of arthritis except in the
presence of MC [7]. Joint
pain and stiffness usually
affect the proximal
interphalangeal,
metacarpophalangeal joints,
and knees and are
precipitated by cold
exposure. Generalized
weakness hampers the quality
of life. An SVR may reduce
the severity, but fatigue
may continue as long as
cryoglobulins are present.
Neurologic manifestations of
the HCV-MC complex are
usually confined to the
peripheral nervous system
and are reported in over 80%
of these patients [2].
Sensory deficiencies of the
lower legs are more common
than motor losses.
Polyneuropathies are often
bilateral but may be
asymmetrical, producing
painful paresthesias or
hypoesthesia. The sensory
symptoms may persist for
months to years before any
motor defect becomes
clinically evident.
Electromyography can
demonstrate an axonal
involvement of the sensory
potentials and later a delay
in motor conduction. Motor
abnormalities alone have not
been reported. Nerve
biopsies may reveal a loss
of myelinated fibers in
axons and mononuclear
infiltrates around the small
vessels with deposits of
mixed cryoglobulins
producing the vasculitis
[8]. In a few cases
complement components, C3,
C4, and C1q, have been
found. HCV without MC can
also be associated with
peripheral neuropathies, and
HCV RNA strands can be seen
in perineural cells.
An elevated RF is seen in
over 70% of HCV patients and
can be a useful screening
test for those suspected of
having MC. In these
patients, the diagnosis of
MC requires the measurement
of cryoglobulins. However,
because many laboratories do
not perform this test
routinely, false-negative
results exist and the
diagnosis can still be made
in the presence of other
positive clinical and
laboratory findings. The
majority of patients with
HCV-associated MC have
significant hepatitis or
advanced fibrosis. However,
MC has been reported in
those with normal liver
enzymes and mild histology
when HCV is diagnosed early
in the course of the disease
[7].
Treatment options for
HCV-associated MC include
corticosteroids, cytotoxic
agents, plasmapheresis, and
direct antiviral therapy
with IFN and ribavirin [10].
The objective is to reduce
the formation and
inflammation associated with
cryoglobulins. Because the
formation of cryoglobulins
is in part related to
interaction of HCV RNA and
its antibodies, treatment
with IFN to eradicate HCV
RNA is the logical approach.
Experience with IFN has been
limited. Overall, clinical
improvements in proteinuria,
renal function, vasculitis,
and purpura are reported in
patients who achieve
virologic response [10].
Unfortunately, relapse is
common when therapy is
discontinued. Although the
sustained loss of HCV RNA is
higher with IFN and
ribavirin combination
therapy, there are few data
related to patients with MC.
We and others have had
success in controlling MC
symptoms with long-term
maintenance IFN. With the
development of pegylated IFN,
this may now be a viable
long-term option in selected
patients. In those that
present with an acute
nephritic syndrome and signs
of acute vasculitis, a more
aggressive approach using
pulse corticosteroids and
cyclophosphamide with or
without plasmapheresis has
been suggested.
Moderate degree of
association
Whereas extrahepatic
diseases associated with MC
have a strong relationship
with HCV, many other
disorders without MC have
been reported with less
proof, mostly in isolated
case reports. Although
periarteritis nodosum (PAN)
is rarely associated with
HCV, in contrast with HBV,
the differential diagnosis
may be difficult [8]. PAN is
a life-threatening disease
with systemic necrotizing
vasculitis involving and
occluding medium-sized
vessels with a mixed
inflammatory infiltrate
[12]. Cerebral angiitis,
ischemic abdominal
vasculitis with intermittent
pain, and hypertension with
renal insufficiency result
in a confusing pattern. The
neuropathy is multifocal,
with severe sensorimotor
involvement. The mechanism
for the association has not
been established, and there
are clear-cut pathologic
differences from HCV-MC
vasculitis.
A recent meta-analysis of
patients with B-cell
non-Hodgkin's lymphoma (NHL)
reported an elevated
prevalence of HCV of 15%,
suggesting that HCV had a
causative role in certain
forms of lymphoma. Splenic
lymphoma with villous
lymphocytes (SLVL) is an
indolent chronic B-cell
lymphoproliferative disorder
similar to NHL. In a French
study of a group of patients
with SLVL, nine had
concomitant HCV, were
treated with combined IFN
and ribavirin without
chemotherapy, and had a
hematologic response along
with the viral response
[15]. HCV RNA has been
isolated from infected lymph
nodes in patients with a
low-grade lymphoma called
immunocytoma. HCV has also
been recovered from the
gastric mucosa of other
low-grade lymphomas called
marginal cell lymphomas
(MALT) [16]. HCV patients
with these MALT lymphomas
are reported to have a
10-fold increased risk of
developing B-cell NHL. The
association of HCV with
these low-grade lymphomas
suggests a causative role
for HCV, but that role is
still not proven.
A possible mechanism of
disease has been proposed
indicating that HCV
stimulates the immune
system, producing
cryoglobulins that
predispose to a
lymphoproliferative
disorder. HCV patients are
more likely than control
subjects to have
overexpression of the
anti-apoptotic bcl-2
protooncogene, and this may
play a role in lymphoma
development [17]. The
association of HCV with
B-cell NHL remains in
question. Viral replication
has not been proved to occur
in normal B cells, and the
prevalence of B-cell NHL is
low in long-term follow-up
of HCV-MC patients.
Sicca syndrome was
considered a direct
manifestation of HCV
infection because both
conditions have high
concentrations of MC. Both
disorders have a high
incidence of lymphocytic
sialadenitis (58%),
according to Haddad et al.
[18]. Only 30% of HCV
patients with sialadenitis
have xerostomia, and none
have xeroopthalmia or SSB
antibodies, which are
typical in SjAgren
syndrome [19]. Salivary
biopsies in HCV patients
demonstrate changes that are
different from those found
in SjAgren syndrome and
similar to many viral
infections. These findings
include pericapillary
lymphocytic infiltration
with no damage to the
glandular structures [20].
SjAgren syndrome does not
respond to anti-HCV therapy
even after SVR. Polymerase
chain reaction studies have
demonstrated HCV in tears
and saliva but not in the
glandular tissue of the
salivary gland [20]. Studies
with transgenic mice have
demonstrated that E1 and E2
glycoproteins have a direct
effect in producing
sialadenitis [21]. Clinical
differences between patients
with SjAgren system and
those with HCV-induced sicca
syndrome include male rather
than female predominance,
low association with HLA
DR3, and absence of serum
antinuclear antibodies.
Porphyria cutanea tarda
(PCT) is a cutaneous disease
process associated with
photosensitizing action on
accumulated porphyrins in
the skin, resulting in
increased skin fragility,
hypertrichosis of
light-exposed areas,
chloracne, hyperpigmentation,
sclerodermoid changes,
dystrophic calcifications
with ulcerations, scarring,
alopecia, and onycholysis
[2, 22*, 23**].
Traditionally these findings
are manifest clinically by
the blisters, vesicles,
and/or milia seen on the
dorsal aspect of hands and
other sun-exposed areas
(Fig. 2).
The proposed mechanism of
injury for this phenotypic
expression is from the
accumulation of uroporphyrin
and other highly
carboxylated porphyrins in
the epidermis and their
resultant photoactivation.
As these oxidized
metabolites diffuse from the
plasma into the upper
dermis, because of their
water-soluble nature, they
are exposed to
photoactivation, creating
reactive oxygen singlets
that in turn form free
radicals. These free
radicals are then involved
in the activation of the
local complement cascades,
resulting in the splitting
of the dermis through bullae
formation in the
subepidermal layer [24].
Bullae formation and
resultant splitting are the
phenotypic expression that
identifies most patients as
carriers of the genetic
defect that reduces the
activity of uroporphyrinogen
decarboxylase (URO-D).
Many disease processes are
speculated to propagate the
phenotypic expression of
sporadic PCT by hypothesized
mechanisms that remain
poorly understood. It is now
relatively well established
that there is a definitive
link between HCV infection
and PCT [23**]. The
literature, while sparse on
treatment options and
mechanisms of injury in
HCV-induced PCT, repeatedly
illustrates evidence that
HCV infection is related to
an increased phenotypic
expression of PCT when
compared with that seen in
the general population. It
is also suggested that the
prevalence of HCV infection
in phenotypic PCT is more
complex than was initially
expected, based on the wide
variance in the proportion
of PCT patients in their
coinfection with HCV based
on geographic location. The
presence of iron overload
together with HCV suggests
the possibility of HLA-linked
hereditary hemochromatosis
and HFE gene analysis for
C282Y and H63D mutations
should be performed [25].
In the United States, HCV
infection is found in almost
60% of patients with PCT,
compared with 2% prevalence
in the general population
[24]. Patients with HCV
infection with a genetic URO-D
deficiency are at risk not
only for dermal
manifestations; mounting
evidence also suggests that
the concomitant HCV
infection superimposed on
PCT results in earlier liver
dysfunction. This
accelerated dysfunction not
only manifests itself
through earlier expression
of phenotypic PCT, when
compared with
non-HCV-infected PCT
patients, but is also seen
as worse histology on
biopsy. The link to earlier
phenotypic expression in
HCV-infected patients
invariably leads back to an
increase in hepatic
porphyrin levels. This
increase in porphyrin levels
is also believed to have an
increased carcinogenic
effect, as demonstrated by a
15% prevalence of
hepatocellular carcinoma
development within a decade
after phenotypic expression
of PCT [26].
Although the exact mechanism
of how HCV infection and PCT
phenotypic expression are
linked has not yet been
established, there has been
no evidence linking the two
in a reverse fashion. PCT
has not been shown to
increase the likelihood of
HCV infection [27]. The most
reasonable hypothesis set
forth in the literature is
that the phenotypic
expression of PCT is not
solely catalyzed by an HCV
infection but rather
requires a combination of
genetic, infectious, and
environmental factors. HCV
seems to provide an
accelerating catalyst to
this system by allowing the
decompartmentalization of
hepatocytic iron, giving
rise to "free iron." This
free iron in an oxidized
form further inhibits the
conversion of
uroporphyrinogen to
coproporphyrinogen by URO-D,
allowing for
uroporphyrinogen to undergo
oxidation to uroporphyrin
[28]. This buildup of
porphyrin, and eventual
leakage out of the
hepatocytes, results in an
increase in plasma porphyrin
levels. These are then
transported to and absorbed
by peripheral tissues where
they are sun-activated, and
phenotypic expression is
observed.
Although modifications to
lifestyle habits, such as
sun avoidance, long-sleeve
clothing, and ultraviolet
protection with sun blocks,
are used to help decrease
the incidence of phenotypic
PCT expression, the majority
of effective treatment has
focused on porphyrin
reduction, mainly through
depletion of iron store. The
goal of therapy is to reduce
total oxidized iron levels
to prevent the further
inhibition of an already
genetically predisposed
decreased functioning of URO-D.
The reduction of free iron
and prevention of hepatic
uroporphyrin overload
prevent the acceleration of
phenotypic PCT expression
and hepatic injury. To this
end there have been three
major modalities of
treatment: venesection with
total body iron depletion,
low-dose chloroquine
therapy, and chelation with
desferrioxamine [23]. The
use of alcohol or estrogens
should also be avoided [7].
Mild degree of
association
Thrombocytopenia is noted in
about 41% of HCV patients
and may result from
hypersplenism,
autoantibodies, or a defect
in thrombopoietin. This
defect is inversely
correlated with hepatic
fibrosis. Anti-HCV
antibodies were found in 19%
of patients with immunologic
thrombocytopenia [29].
Antiplatelet IgG was noted
in 88% of patients with HCV
and in 47% of patients with
HBV [30]. In a few patients
with HCV and
thrombocytopenia, IFN
therapy led to an increase
in platelets along with a
viral response. These
findings suggest a direct
effect of HCV on platelet
formation, but usually the
thrombocytopenia precedes
the HCV by a considerable
time.
Type 2 diabetes mellitus was
found in 21% of a group of
HCV patients, compared with
only 12% of a matched group
of HBV patients, whereas the
prevalence of cirrhosis was
comparable [31]. No
significant difference was
shown between the groups in
the absence of cirrhosis,
and HCV did not predict
glucose intolerance in the
absence of cirrhosis.
Autoantibodies also were not
increased in HCV without
cirrhosis. HCV RNA has been
found in the pancreas,
suggesting a direct effect
on beta-cell dysfunction,
and may cause some of the
observed insulin resistance
together with cirrhosis
[32]. Antiviral therapy on
glucose tolerance brings
mixed results. An increase
in hepatic clearance may
cause a decrease in free
fatty acids but no change in
insulin response. IFN may
further an autoimmune
process against beta-cells,
inducing type 2 diabetes
mellitus in genetically
susceptible patients.
Autoimmune thyroiditis may
be the most common
autoimmune disorder found in
HCV patients [7].
Antithyroid antibodies are
particularly prevalent in
older women with or without
HCV. Patients with HCV have
a higher thyroid-stimulating
hormone level and
significantly lower T3 and
T4 on average compared with
a control group or patients
from an iodine-deficient
area [33]. Hypothyroidism is
more frequent in both sexes
with HCV than in control
patients but especially in
patients with positive
antithyroid antibodies prior
to IFN treatment. IFN may
exacerbate an underlying
thyroid immune disease, and
thyroid dysfunction may
improve when the antiviral
therapy is discontinued.
Consequently, all patients
and especially women should
have thyroid antibodies
studied prior to IFN
therapy. Whether HCV is a
direct cause for
hypothyroidism is still
controversial.
Lichen planus (LP) has been
reported to be associated
with many chronic liver
diseases. The prevalence of
HCV antibodies in
association with LP has been
reported to be 29%, whereas
with HBV it was 12% and with
hepatitis A virus it was
16%. Marked variation is
shown in reports from
different geographic areas:
62% in Japan, 4% in northern
France, and 0% in Great
Britain. A causative role
for HCV is uncertain, but
the LP lesions may progress
with IFN therapy and improve
with the cessation of
antiviral therapy [34, 35].
The lesions progress with
the duration of the HCV
infection. They have a
generalized distribution and
a high incidence of oral
mucocutaneous involvement.
The lesions are described as
flat-topped, violaceous
pruritic papules (Fig. 3).
LP may be initiated through
a cellular immune response,
but the actual mechanism is
unknown.
Treatment
In the presence of
significant viremia,
extrahepatic problems
require adequate treatment
with an appropriate
pegylated IFN and ribavirin
protocol. There are several
caveats to be considered.
IFN therapy may increase the
level of autoantibodies and
confuse HCV with autoimmune
hepatitis. Usually the
antibodies decrease along
with the viral load. Fatigue
and depression may increase
during therapy and may not
improve in conjunction with
SVR (note from Jules Levin:
fatigue was the main side
effect I experienced while
taking therapy, but since
completing therapy with SVR
2 years ago pre-therapy
fatigue and cognitive
impairment I was
experiencing is greatly
improved, I have not felt
better in many years).
Hematologic decreases may be
improved with IFN, but they
usually become more severe
and require close
observation. IFN may
exacerbate thyroid
dysfunction, but it usually
improves when therapy is
discontinued; therefore,
thyroid supplements need
monitoring while patients
are on anti-HCV therapy.
Finally, in genetically
susceptible patients, IFN
may cause autoimmune damage
to the beta cells of the
pancreas, producing overt
diabetes. Adequate treatment
of HCV requires monitoring
of these extrahepatic
manifestations.
Conclusions
Extrahepatic manifestations
of chronic HCV are common
and have been reported in as
much as 36% of HCV-infected
patients. Most symptoms are
nonspecific and include
fatigue and arthralgias.
True extrahepatic syndromes
can be divided into those
with a high degree and those
with a more moderate or mild
association with HCV. The
most prevalent extrahepatic
disease with the highest
degree of association with
HCV is EMC with skin,
neurologic, renal, and
rheumatologic complications.
Non-cryoglobulin diseases
with a less definite
relationship to HCV include
systemic vasculitis, splenic
lymphoma, porphyria cutanea
tarda, and the sicca
syndromes. As such, testing
for HCV should be done in
individuals who present with
these conditions. Treatment
of these extrahepatic
manifestations is directed
at the HCV virus itself as
well as the extrahepatic
organ affected and often
requires a multidisciplinary
approach. |
|
|
