The Reproductive Care of Women Living With Hepatitis C Infection
III. Virology, Clinical Manifestations,
Course of Disease
There are very few studies defining the natural history of HCV
infection, and those available do not always take into account the
genotype, geographical area or therapeutic intervention. The long
evolution of the disease also makes study design difficult.Despite
these limitations, a significant amount of information has been
accumulated.
A.The Oragnism
Hepatitis C virus is a single stranded RNA, enveloped virus from
the Flaviviridae family. It is characterized by a wide range of
genomic heterogeneity and multiple distinct types (Table VII). For
each of these genotypes several subtypes exist, differing from each
other by about 20 percent of their sequence. The generally accepted
classification scheme describes six major genotypes and over 30
subtypes.3,83,84 In North America types 1a and 1b are
the most common in non-migrant people, but there are regional variations.
Immigrants to Canada may have acquired different genotypes in their
country of origin. The subtypes are also geographically distributed.
After infection the virus has been shown to mutate into genetically
distinct populations referred to as "quasi species," which
carries important consequences for the development of chronic disease,
immune response, and vaccine development. HCV does not seem to induce
an effective, protective immune response.
HCV is easily destroyed by heat and is probably quite an unstable
virus. Although survival in the environment is not known, the modes
of transmission do not suggest fomite survival.
B. Natural History
The natural history of HCV infection is complex. Due to the paucity
of symptoms in the acute phase, early diagnosis of the disease is
often not possible. In addition, most infected patients remain asymptomatic
for years. In general, the course of HCV infection is slowly progressive.
About 15 percent of HCV infected individuals recover spontaneously;
an additional 25 to 30 percent have an asymptomatic illness with
persistent normal aminotransferases and generally benign histological
lesions; hence about 40 percent of patients recover or have a benign
outcome.3 For some, however, HCV is a chronic, debilitating,
symptomatic disease.
TABLE VII : CHARACTERISTICS OF HCV
single stranded RNA virus
enveloped
six major genotypes
at least 30 subtypes
produces "quasi species" or diverse populations in
the same individual patient
1. Course of infection
See Figures 2 and 3.
2. Pathology
a) Liver biopsy: liver biopsy features may be categorized
into lobular and portal tract changes. Tissue is described by grade
of inflammation (mild, moderate, severe) and stage of fibrosis from
0 (no fibrosis) to 4 (cirrhosis).
lobular changes suggest widespread liver damage. HCV antigen
and RNA can be isolated in the cytoplasm of infected cells. Cellular
atypia may also be present and may
represent a precursor to the development of carcinoma.
portal tract changes include nodular aggregates of lymphocytes
in germinal centres and bile duct lesions. The basic cellular
damage from HCV probably occurs through an immunologic pathway,
although a direct cytopathic effect may play a more minor role.
b)Liver function: most patients with chronic HCV will have
raised aminotransferase levels, although this does not appear to
correlate with disease severity or progression. Thirty percent of
patients with HCV RNA may, however, have normal transaminases, and
despite this still have significant histopathologic changes on liver
biopsy. The longterm prognosis for this particular group remains
uncertain but would appear to be less severe.
C. Sequelae
1. Hepatic complications
a)Cirrhosis: cirrhosis will occur in about 20 percent of
chronically infected patients. The mean interval between exposure
and development of cirrhosis ranges from three to 44 years and appears
to be longer in patients with histologically diagnosed mild activity
compared to those with a higher grade of inflammation, especially
if severe. It is generally agreed that cirrhosis is a late manifestation
and unlikely to occur before the first decade post-exposure. Liver
biopsy is useful to stage disease in those with HCV RNA and elevated
transaminases, and is the only reliable method to diagnose cirrhosis
as there may well be no other clinical evidence. The presence of
severe fibrosis and necroinflammatory changes is predictive of the
development of cirrhosis.3,58 The prognosis is also linked
to the severity of fibrosis as a function of time or duration of
disease. The main complication of cirrhosis is portal hypertension
leading to bleeding œsophageal varices, ascites, and hepatic
failure.85-87
b)Hepatocellular carcinoma: hepatocellular carcinoma may
develop with further disease progression as a late and infrequent
manifestation in cirrhotic patients. It occurs with an annual incidence
of approximately one percent of those with cirrhosis, although rates
vary with geographical location and have been reported as high as
11 percent. It has been shown to occur from 15 to more than 45 years
post-exposure. The pathophysiology remains unclear, with repeated
necroinflammatory insults and a direct carcinogenic effect of HCV
both being postulated.88
2. Extra-hepatic complications
HCV infection has also been associated with several conditions,
possibly by triggering an autoimmune response:
cryoglobulinaemia (essential mixed type II)
membranous glomerulonephritis
porphyria cutanea tarda
aplastic anaemia
Associations have also been suggested with Sjögren's
disease, Mooren's corneal ulcer, B-cell non-Hodgkin's
lymphoma, thyroiditis, and immune thrombocytopenic purpura.1,89-91
D. Co-Factors
The natural history of HCV may be influenced by the presence of
viral and host factors.84,92
1. Viral load/viraemia
There is no clear correlation between the level of HCV RNA, genotype,
and disease progression. Quantitative HCV RNA levels and genotype
are used to determine treatment protocol. In general, patients with
higher levels of viraemia (more than 2 million copies/ml) are relatively
less likely to respond to therapy, as are those with genotype 1
compared to genotype 2 or 3. Therefore, duration of treatment for
types 2 or 3 is six months regardless of the level of viraemia.
In patients with type 1, current data suggests that six months treatment
is sufficient if there is a low level of viraemia, but 12 months
is required if high.84,92
2. Histology
Higher necroinflammatory grading or fibrosis appears to be associated
with accelerated progression to cirrhosis. In cases of severe inflammatory
changes, a risk as high as 90 percent for the development of cirrhosis
has been reported.84,92
3. HIV co-infection
Recent reports have shown the negative effects of co-infection with
HIV and are thought to indicate a poorer prognosis for both diseases.
It is suggested that, in the presence of HIV, HCV behaves as an
opportunistic infection in which progressive liver disease is the
principal manifestation. It has been shown that HIV positive patients
who acquire HCV have a higher risk of developing progressive liver
disease, and those with AIDS-defining immunodeficiency higher still.
In addition, patients co-infected with HCV and HIV who also have
progressive liver disease have a more rapid progression to AIDS.
The interactions between these two viruses are complex and should
be managed by experts in the field.58,84,92
4. Alcohol
Consumption of alcohol is the most important external cofactor for
disease progression, both in biochemical and histological severity.
Consumption of more than two units per day increases the rate of
progression to cirrhosis threefold. For this reason, abstinence
is strongly advised. (A unit is equivalent to one glass of wine
or a half pint of beer.)
E. Genfder and Age Effects
1. Gender
In most adult studies, male sex has been associated with greater
disease severity. The potentially more benign course in young women
is supported by two studies of women who became infected following
Rh immunoprophylaxis prior to the availability of a purification
process.82,92 The researchers reported that although
most infected women developed chronic hepatitis, it was usually
not severe and the incidence of complications such as cirrhosis
was very low, even after many years of follow-up (Table VIII).
2. Age
Advancing age has been associated with increased histological severity
and a possible decreased interval to the development of late manifestations
such as cirrhosis.82
F. Pregnancy
Currently there is no data to suggest that pregnancy alters the
course of HCV. Indeed, most pregnant women are asymptomatic and
only a minority (10%) have elevated transaminases. It has been hypothesized
that endogenous production of interferon, partly by the fetoplacental
unit, may account for the lower levels of transaminases in pregnant
women.5,96-100 There does not appear to be an increase
in frequency of adverse pregnancy outcomes in women with HCV. Vertical
transmission, however, is a risk, and so far it would appear that
most children infected in this way develop chronic hepatitis.
G. Infection in Children
Infection in children is acquired either by transfusion (although
this has become very rare in the era of systematic screening for
HCV infection in all blood donations) or by perinatal transmission
from an infected mother. Recent studies with long-term follow-up
of children infected by either mechanism have shown that infection
in children is associated with milder disease than infection in
adults.5,100-102 The clinical course in these children
is characterized by low or normal transaminase levels, less severe
histological changes and a lower percentage with persistent presence
of HCV RNA. Follow-up in some of these studies is close to twenty
years. However, some children have fibrosis on liver biopsy and
fibrosis progresses with age and duration of illness. Thus, it is
possible that some individuals infected in early childhood will
eventually progress to end stage liver disease.101,103,104
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