The
average
time
from
HCV
exposure
to
seroconversion
is
approximately
50
days,
although
it
can
be
as
long
as
nine
months
(Tremolada
1991;
MJ
Alter
1992).
http://www.thebody.com/tag/hepatitis/history.html
The
Hepatitis
Report
Natural
History,
Clinical
Manifestations,
and
Prognostic
Indicators
of
Disease
Progression
and
Survival
of
Hepatitis
C
Virus
(HCV)
Infection
By
Michael
Marco
The most accurate means of determining the entire spectrum of outcomes of HCV infection would be to identify a large cohort at a time of initial infection; to select a carefully matched seronegative control group who, like the seropositive group, could be maintained under active surveillance for periods of 30 years or more; and to omit therapy that might alter outcome and hence modify natural history. Obviously, these conditions cannot be met and, therefore, the desired information may never be forthcoming.
-- Leonard Seeff, The Natural History of Hepatitis C -- A Quandary
Introduction Numerous
HCV
natural
history
studies
have
attempted
to
detail
the
course
of
HCV
infection,
yet
most
have
been
unable
able
to
chart
disease
progression
from
initial
infection
to
end-stage
disease,
and
only
one
has
more
than
25
years
of
follow-up
(Seeff
2000b).
Long-term,
accurate
natural
history
data
are
needed
to
better
understand
the
pathogenesis
of
the
disease
and
to
determine
which
patients
need
treatment
now,
which
ones
can
wait
for
more
effective
treatment,
and
which
ones
will
probably
never
need
treatment.
Clinical
Features
and
Outcome
of
Acute
HCV
Acute
HCV
infection
most
often
exhibits
no
clinical
symptoms:
60%
to
75%
of
individual
are
asymptomatic;
20%
to
30%
become
jaundiced;
and
10%
to
20%
have
symptoms
including
fatigue,
nausea,
and
vomiting
(Dienstag
1983;
Aach
1991;
Koretz
1993).
In
those
who
develop
jaundice,
peak
bilirubin
levels
are
usually
less
than
12
mg/dl
(mean:
8.4
mg/dl)
and
levels
appear
to
resolve
in
less
than
four
weeks
(Esteban
1999).
Fulminant
hepatic
failure
with
primary
HCV
infection
is
extremely
rare.
Approximately
20%
of
newly
individuals
have
symptoms
that
arise
before
the
seroconversion
to
anti-HCV
occurs
(antibody-positive)
(Koretz
1993).
The
average
time
from
exposure
to
seroconversion
is
approximately
50
days,
although
it
can
be
as
long
as
nine
months
(Tremolada
1991;
MJ
Alter
1992).
During
acute
infection,
a
person's
aminotransferase
(ALT)
levels
(liver
enzymes)
rise
to
200600
IU/I,
but
in
20%
of
cases,
peak
ALT
levels
exceed
1000
IU/l
(Esteban
1999).
There
is
often
an
episodic,
fluctuating
pattern
of
ALT
levels
during
the
first
few
months,
where
levels
flare
to a
10-
to
15-fold
increase.
Approximately
25%
of
patients
develop
a
sustained
plateau
pattern
where
ALT
levels
remain
below
450
IU/l
for
many
months.
In
others,
ALT
level
can
normalize
(suggesting
recovery),
yet
flare
up
again
within
months
to
years.
This
pattern
is a
tell-tale
sign
of
chronic
infection
with
HCV
and
indicates
a
need
for
ongoing
ALT
monitoring
(MJ
Alter
1992;
Esteban
1999).
More
than
12
months
after
acute
infection,
ALT
levels
will
continue
to
be
elevated
in
about
60%
of
individuals
(Esteban
1998).
Continued
normalization
of
ALT
levels
--
termed
"biochemical
recovery"
--
does
not
always
mean
a
loss
of
anti-HCV
or
absence
of
HCV
RNA
(MJ
Alter
1992).
Likewise,
continued
abnormal
ALT
levels
with
anti-HCV
positivity
does
not
necessarily
mean
that
a
person
is
chronically
infected
with
HCV.
Fifteen
to
twenty-five
percent
of
acutely
HCV-infected
individuals
will
clear
their
infections
(Shakil
1995).
Complete
resolution
of
HCV
infection
is
defined
as
both
the
absence
of
HCV
RNA
in
serum
and
a
normalization
of
serum
ALT
level.
Shakil
and
colleagues
from
the
National
Institutes
of
Health
(NIH)
documented
the
rate
of
chronic
HCV,
using
PCR
and
bDNA
assays,
and
histologic
(liver
cell)
damage
in
60
anti-HCV
positive
individuals
with
chronic
hepatitis
(Shakil
1995).
Tabled
below
are
the
results
of
the
60
patients
equally
divided
into
three
groups:
group
1:
normal
ALT
levels;
group
2:
elevated
ALT
levels
less
than
twice
the
normal
range;
and
group
3:
levels
more
than
twice
the
normal
range.
| HCV Virologic & Histologic Confirmation of 60 Anti-HCV Volunteer Blood Donors |
|
Group I
N=20 |
Group II
N=20 |
Group III
N=20 |
P |
| Baseline ALT |
42 (13-88) |
80 (47-125) |
125 (40-308) |
<.0001 |
| Virology |
| HCV RNA PCR+ |
13 (65%) |
19 (95%) |
19 (95) |
0.0009 |
| HCV RNA bDNA+ |
12 (60%) |
18 (90%) |
17 (75%) |
0.091 |
| Histology |
0.018 |
| Normal |
3 |
0 |
0 |
|
| Nonspec. Changes |
3 |
0 |
0 |
|
| Chronic Hepatitis |
| Mild |
8 |
16 |
9 |
|
| Moderate |
6 |
3 |
9 |
|
| Severe |
0 |
1 |
1 |
|
| Active Cirrhosis |
0 |
0 |
|
|
| (Shakil 1995) |
The
presence
of
viremia
(HCV
RNA
in
blood)
in
all
groups
did
not
correlate
with
age,
route
of
transmission,
or
duration
of
infection.
Nonetheless,
those
who
were
HCV
RNA-negative
were
more
likely
to
have
persistently
normal
ALT
levels
(78%)
compared
to
those
who
were
HCV
RNA-positive
(20%).
Likewise,
most
of
those
who
were
HCV
RNA-negative
had
either
normal
liver
histologic
findings
or
only
mild
changes
(Shakil
1995).
Some
individuals
(~15%)
who
test
HCV
RNA-positive
during
acute
or
post-acute
HCV
infection
may
eventually
become
undetectable
and,
conversely,
some
(~19%)
who
initially
test
HCV
PCR-negative
may
become
detectable
at a
later
date.
Villano
and
colleagues
from
Johns
Hopkins
studied
HCV
RNA
patterns
in
43
HCV
seroconverters
(documented
by
EIA-2
and
RIBA-2)
who
were
followed
for
72
months
(Villano
1999).
Six
(14%)
patients
had
documented
viral
clearance
(undetectable
HCV
RNA,
<500
copies/mL)
between
one
and
two
years;
one
patient
was
initially
undetectable
for
HCV
RNA
and
remained
negative.
Two
of
the
patients
who
cleared
virus
had
~1
million
copies/mL
of
virus.
Factors
associated
with
viral
clearance
were:
white
race
(P =
0.004);
jaundice
(P =
0.003);
and
lower
peak
viral
titers
(P =
0.003).
The
presence
of
HCV
RNA
did
not
always
precede
the
development
of
antibodies:
48%
had
HCV
RNA
at
their
first
seroconversion
visit;
33%
were
HCV
RNA-positive
a
median
3.8
months
before
seroconversion;
and
19%
were
HCV
RNA-detectable
a
median
15.3
months
after
estimated
date
of
seroconversion.
The
fact
that
a
person
who
may
initially
test
qualitatively
HCV
RNA-negative
(no
detection
of
HVC
in
serum)
but
later
become
positive
suggests
that
"in
clinical
practice,
virologic
outcome
must
be
determined
by
long-term
follow-up,
not
a
single
HCV
RNA
level"
(Villano
1999).
One
significant
finding
in
this
study
deserves
comment.
Seventy-four
percent
of
the
anti-HCV-positive
patients
in
this
study
(the
majority
with
a
history
of
intravenous
drug
use
(IVDU))
had
been
evaluated
by a
physician
during
their
seroconversion
intervals,
yet
only
a
few
were
recognized
as
having
HCV
or
were
screened
for
it.
In
this
case,
one
cannot
say
that
hepatitis
was
not
detected
because
of
limited
access
to
health
care.
Even
though
HCV
does
not
present
with
severe
symptoms,
this
routine
failure
to
diagnosis
HCV
in
patients
known
to
be
at
high
risk
indicates
a
striking
lack
of
awareness
by
health
care
providers
about
HCV
and
its
epidemiology.
Chronic
Infection
Data
from
various
studies
indicate
that
75-85%
of
individuals
with
acute
HCV
infection
will
become
chronically
infected
(MJ
Alter
1992;
Shakil
1995;
Villano
1999).
The
reason
for
such
a
high
rate
of
chronicity
is
not
completely
understood.
Some
studies
suggest
that
HCV
persistence
is
related
to
the
high
mutation
rate
of
HCV
and
the
continual
turnover
of
complex
viral
quasispecies
that
are
able
to
evade
the
immune
response
of
the
host
(Tsai
1998;
Ray
1999).
Farci
and
colleagues
from
the
University
of
Cagliari
and
Robert
Purcell's
NIH
laboratory
recently
published
data
which
suggest
that
resolution
of
acute
hepatitis
is
associated
with
relative
evolutionary
stasis
of
quasispecies,
but
progression
to
chronicity
is
correlated
with
genetic
evolution
of
HCV
(Farci
2000).
Only
60%
to
70%
of
chronically
infected
individuals
will
have
persistent
or
fluctuating
ALT
elevations;
the
other
30%
to
40%
will
have
normal
ALT
levels
throughout
the
course
of
their
infection.
Two
studies,
one
by
Shakil
and
colleagues,
the
other
by
Pastore
and
colleagues
have
documented
that
relatively
low
(13-135)
or
normal
ALT
levels
during
acute
infection
were
prognostic
indicators
predicting
loss
of
HCV
infection
(Pastore
1985;
Shakil
1995).
In
at
least
four
other
natural
history
studies,
however,
ALT
levels
were
not
found
to
be
predictive
of
clearance
(Mattsson
1989;
Esteban
1991;
MJ
Alter
1992;
Villano
1999).
Except
for
the
Villano
study
mentioned
above,
which
noted
that
whites
had
a
higher
rate
of
clearance
than
blacks
(80%
of
the
subjects
were
black),
and
a
small
Swedish
study
(N =
37)
by
Mattsson
that
documented
an
increased
rate
of
clearance
among
patients
under
30
years
old,
no
other
major
natural
history
studies
have
found
any
prognostic
factors
for
disease
clearance
(Mattsson
1989;
Villano
1999).
In
2000,
it
is
still
a
guessing
game
as
to
who
will
develop
chronic
infection.
According
to
Juan
Ignacio
Esteban,
"No
clinical,
biochemical
or
virological
feature
can
predict
the
outcome
of
infection
in a
given
individual"
(Esteban
1999).
A
liver
biopsy
gives
the
most
accurate
information
about
the
degree
of
liver
injury
associated
with
HCV
infection.
There
are
many
complex
and
detailed
staging
and
scoring
systems
for
liver
biopsies
(e.g.,
Knodell
score,
METAVIR
fibrosis
score).
According
to
Leonard
Seeff,
natural
history
studies
have
used
one
of
three
evaluation
strategies
(Seeff
1997,
2000a):
- Prospective studies starting with disease onset which have a low documentation of morbidity (symptoms, cirrhosis) and mortality (hepatic/liver failure, HCC). Follow-up tends to be short (8 to <20 years) and sample size is usually small.
- Prospective studies of patients (usually older than 45 years of age) with already established chronic liver disease who have been referred to liver disease units/specialists. These tend to have shorter follow-up and referral bias with far sicker patients.
- Retrospective/prospective (non-concurrent prospective) studies of recipients of HCV-contaminated immunoglobulin and transfused blood. These usually have an ~20 year follow-up period and contain matched non-hepatitis controls.
One
of
the
most
important
prospective
natural
history
studies,
the
NIH
Prospective
Study
of
HCV-Infected
Donors,
was
recently
published
(HJ
Alter
1997).
It
included
280
HCV
RNA-
positive
blood
donors
followed
for
a
median
of
20
years.
ALT
levels
were
repeatedly
normal
in
17%;
45%
had
<2X
the
upper
limit
of
normal;
and
38%
had
a
least
one
reading
5X
the
upper
limit.
Liver
biopsies
were
performed
on
81
of
280
patients,
and
a
probable
date
of
exposure
could
be
ascertained
in
74
of
the
81.
The
chart
below
represents
biopsy
findings
according
to
time
from
exposure:
Only
1.3%
had
histologic
evidence
of
severe
hepatitis
and
cirrhosis
following
a
mean
interval
of
18
years
from
time
of
exposure.
According
to
Harvey
Alter,
"Liver-related
mortality
or
severe
morbidity
is
less
than
10%
in
the
first
two
decades
after
infection."
(Alter
1997)
Koretz
and
colleagues
from
UCLA
documented
a
more
progressive
clinical
course
in
their
study
of
80
recipients
of
HCV
transfused
blood
who
were
followed
for
14
years
(Koretz
1993).
After
16
years
of
known
infection,
10%
had
HCV-related
symptoms;
18-20%
had
biopsy-proven
cirrhosis;
1.3%
developed
hepatocellular
carcinoma
(HCC;
liver
cancer);
and
2.5%
died
of
liver-related
complication.
Cohort
studies
of
chronic
HCV
patients
referred
to
liver-oriented
tertiary-care
centers
suggest
progressive
HCV
disease.
Tong
and
colleagues
followed
131
patients
with
HCV
for
approximately
22
years:
mean
age
at
transfusion
was
35
years,
and
at
time
of
evaluation,
the
mean
age
was
57
years
(Tong
1995).
After
about
four
years
of
follow-up,
over
67%
were
experiencing
HCV-related
symptoms
(specifically
fatigue);
46%
had
biopsy-proven
cirrhosis;
10.6%
had
developed
HCC;
and
15.3
%
had
died
of
liver-related
deaths.
The
accompanying
chart
documents
time
to
hepatic
event:
Two
significant
retrospective
natural
history
studies
were
recently
published
reporting
the
longest
follow-up
yet
of
well-characterized
HCV
infected
cohorts
(Kenny-Walsh
1999;
Seeff
2000b).
The
first,
by
Kenny-Walsh
and
colleagues,
documents
the
clinical
course
of
HCV
in a
group
of
376
HCV
RNA-positive
Irish
women
who
had
been
infected
during
19771978
with
a
batch
of
HCV-contaminated
anti-D
immune
globulin
(Kenny-Walsh
1999).
The
mean
age
of
the
women
at
time
of
infection
was
~28
years,
and
after
17
years
of
living
with
HCV,
the
mean
age
of
at
screening/biopsy
was
45
years.
None
had
received
any
anti-HCV
treatment.
HCV-related
symptoms,
histologic
grade
of
hepatic
inflamation,
and
stage
of
fibrosis
for
the
363
women
who
underwent
biopsies
are
documented
below:
| Symptoms and Histologic Findings in Irish Women ~17 Years Post HCV-infection |
| Variable |
No. of Women |
ALT Level (U/liter) |
|
|
Median |
Range |
| Documented Symptoms (N=376) |
| Reported >1 Symptoms |
304 (81%) |
|
|
| Fatigue |
248 (66%) |
|
|
| Arthralgia or Myalgia |
143 (38%) |
|
|
| Anxiety or Depression |
60 (16%) |
|
|
| Right-upper-quadrant Pain |
23 (6%) |
|
|
| Rashes |
19 (6%) |
|
|
| Histologic Findings (N=363) |
| Grade of Inflammation |
| 0 |
7 (2%) |
24 |
11-66 |
| 1-3 |
150 (41%) |
37 |
10-61 |
| 4-8 |
190 (52%) |
46 |
10-232 |
| 9-18 |
16 (4%) |
80 |
34-381* |
| Stage of Fibrosis |
| No Fibrosis |
177 (49%) |
35 |
10-198 |
| Periorbital or Portal Fibrosis |
124 (34%) |
46 |
10-261 |
| Portal-portal Bridging Fibrosis |
36 (10%) |
53 |
15-381 |
| Portal-central Bridging |
19 (5%) |
100** |
34-232 |
| Probable or Definite Cirrhosis |
7 (2%) |
42 |
10-381 |
* Correlation between grade of inflamation and ALT levels (R=0.23, P<0.001)
**Correlation between stage of fibrosis ALT levels (R=0.30, P<0.001)
(Kenny-Walsh 1999)
|
Compared
to
other
studies,
this
study
appears
to
document
a
slower
progressive
course
of
HCV
infection.
After
17
years
of
infection,
no
fibrosis
was
documented
in
nearly
half
of
the
women,
and
cirrhosis
in
only
2%.
Another
study
from
Germany
of
152
women
infected
with
HCV-contaminated
RH0(D)
immune
globulin
documented
a
similar
clinical
course
(Muller
1996).
After
15
years,
none
of
the
women
were
found
to
have
chronic
active
hepatitis
or
cirrhosis.
There
are
many
speculations
as
to
why
disease
in
this
cohort
of
women
was
so
indolent:
1)
disease
in
women
is
less
progressive
than
in
men;
confirmed
by
Poynard
and
colleagues
(Poynard
1997);
2)
patients
infected
at a
younger
age
fare
better
than
older
ones;
confirmed
by
Tong
and
colleagues
as
well
as
Poynard
(Tong
1995;
Poynard
1997);
and
3)
the
small
amount
of
the
infecting
dose
of
anti-D
immune
globulin
(versus
that
of a
blood
transfusion)
may
have
played
a
role
(Kenny-Walsh
1999).
The
45-year
HCV
natural
history
study
of
8,568
military
recruits
by
Seeff
and
colleagues
reports
the
earliest
confirmed
detection
of
HCV
in
the
United
States
and
has
the
longest
follow-up
of
any
study
published
to
date
(Seeff
2000b).
Originally,
8,568
military
recruits
were
tested
for
group
A
streptococcal
infection
and
acute
rheumatic
fever
between
1948
and
1954.
After
initial
blood
tests,
samples
were
frozen
and
saved
for
45
years.
Seventeen
(0.2%)
individuals
tested
positive
for
HCV
antibodies
on
EIA-3
and
RIBA-3.
While
17
HCV-positive
patients
followed
in a
natural
history
study
may
seem
small,
it's
the
HCV-negative
control
group
of
over
8,000
individuals
(99%
men)
that
makes
this
study
important.
Records
tracking
45
years
of
liver
abnormalities,
disease,
and
death
(using
the
National
Death
Index
Plus
service)
as
well
as
age,
sex,
race,
chart
review,
and
cause-specific
mortality
from
death
certificates
were
available
from
the
Veterans
Affairs'
computer
files.
A
vast
majority
of
the
recruits
were
younger
than
25
years
of
age
at
the
original
blood
draw.
Approximately
90%,
10%,
and
0.5%
were
white,
black
and
Asian,
respectively.
HCV
infection
in
blacks
was
significantly
higher
than
whites:
1.8%
compared
to
0.07%
(RR,
25.9;
CI,
8.4
to
80.0).
The
mean
age
of
the
surviving
cohort,
as
of
January
1997,
was
64.8
years
(95%
were
between
60
and
69
years
of
age).
Eleven
of
the
seventeen
(65%)
HCV-infected
men
were
HCV
RNA-positive;
all
but
one
had
genotype
1b.
Death from All Causes & Liver-disease-related Mortality
after 45 Years Follow-up in 8,568 Military Recruits |
| Event |
HCV+ Group (N=17) |
HCV-Group
( N=8,551) |
RR (95% CI) Ethnically Adjusted |
| Liver Disease |
2 (11.8%) |
205 (2.4%) |
3.56 (0.94-13.52) |
| All Deaths |
7 (41%) |
2226 (26%) |
1.48 (0.8-2.6)* |
| Mean Age at Death |
56.5 years |
54.2 years |
NS |
| Liver Disease-related Death |
1 (16.7%) |
119/1890 (6.3%) |
|
| Death from Liver Cancer |
0 |
9 (0.5%) |
|
| (Seeff 2000b) |
Of
the
seven
deaths
in
the
HCV-positive
group,
only
one
was
due
to
liver
disease.
The
fact
that
the
event
rate
was
so
low
in
the
HCV-positive
group
after
four
decades,
and
that
there
was
little
difference
in
mortality
between
the
groups,
leaves
one
to
believe
that
HCV
is a
less
progressive
disease
than
is
currently
thought.
According
to
Leonard
Seeff,
long-term
natural
history
data
have
revealed
that
only
15%
to
20%
of
HCV-infected
persons
will
eventually
develop
progressive
to
potentially
serious
end-stage
liver
disease
(namely
cirrhosis)
and
that
the
remainder
will
die
of
causes
other
than
liver
disease
(Seeff
2000a).
Prognostic
Factors
for
Fibrosis
Progression:
Good
News
for
the
Non-alcohol-imbibing
Woman
Infected
with
HCV
Before
She
Was
40
A
seminal
natural
history
from
France
by
Poynard
and
colleagues
documents
host
factors,
rather
than
virologic
factors,
as
risks
for
fibrosis
progression
in
untreated
HCV-positive
patients
(Poynard
1997).
Some
2,235
patients
were
selected
from
three
well-characterized
cohorts:
Observatoire
de
l'Hépatite
C
(OBSVIRC);
Cohorte
Hépatite
C
Pitié-Salpêtrière
(DOSVIRC);
and
the
METAVIR.
All
patients
underwent
liver
biopsy,
and
the
METAVIR1
scoring
system
was
used
to
grade
the
stage
of
fibrosis.
Nine
factors
were
assessed
for
effect
on
fibrosis
progression:
age
at
biopsy;
estimated
duration
of
infection;
sex;
age
at
infection;
alcohol
consumption;
HCV
genotype;
HCV
viremia;
method
of
infection;
and
histologic
activity
grade.
Fibrosis
progression
was
defined
as
the
ratio
between
fibrosis
stage
in
METAVIR
units
and
the
estimated
duration
of
infection.
(For
example,
for
a
patient
with
stage
2
fibrosis
who
had
been
HCV-infected
for
eight
years,
the
fibrosis
progression
rate
would
be
0.25
fibrosis
units
per
year.)
The
mean
and
median
rate
of
fibrosis
progression
per
year
for
the
1,157
patients
whose
duration
of
infection
was
known
was
0.252
(95%
CI,
0.227-0.277)
and
0.131
(95%
CI,
0.125-0.143),
respectively.
At
this
rate
the
median
time
to
cirrhosis
was
estimated
as
30
years
(range:
28-32
years);
33%
had
a
median
time
of
20
years
and
31%
will
never
progress
or
will
not
progress
for
at
least
50
years.
Out
of
the
nine
factors
assessed,
three
had
highly
significantly
correlation
with
disease
progression:
gender,
alcohol
consumption,
and
age
at
infection.
Interestingly,
amount
of
HCV
RNA
and
viral
genotype
(i.e.,
1b)
did
not
correlate
significantly
with
disease
progression.
(See
"HCV
Treatments"
chapter,
where
both
are
significant
prognostic
factors
for
success
of
treatment.)
| Multivariate Analysis of the Three Significant Risk Factors for Fibrosis Progression in 1,038 Patients |
| Factor |
Relative Risk |
95% CI |
for Fibrosis Progression in 1,038 Patients |
| Age at Infection (>40 years) |
1.07 |
1.06-1.08 |
<0.0001 |
| Male Sex |
2.66 |
1.90-3.72 |
<0.0001 |
| Alcohol Consumption (>50 grams/day) |
1.49 |
1.18-3.03 |
<0.008 |
| (Poynard 1997) |
| Association between Rate of Fibrosis Progression and Age at Infection |
| Age Group |
Rate of Increase Fibrosis |
| 31-40 Years vs. 21-40 Years |
31% |
| 41-50 Years vs. 31-41 |
45% |
| >50 Years vs. 41-50 |
67% |
| (Poynard 1997) |
Varying
prognostic
factors
predict
a
benign
course
of
HCV
for
some
and
a
severe
one
for
others.
A
female
infected
before
the
age
of
40
who
drinks
<50
grams
(equals
5
glasses)
of
alcohol
per
day
has
an
expected
time
to
cirrhosis
of
42
years
compared
to
15
years
for
a
man
infected
after
the
age
of
40
who
drinks
more
than
50
grams
of
alcohol
per
day.
Selected
Prognostic
Factors
for
Disease
Progression
and
Survival
Age
(Tremolada
1992;
Tong
1995;
Fatovitch
1997;
Poynard
1997;
Neiderau
1998;
Deuffic
1999);
male
gender
(Poynard
1997;
Deuffic
1999;
Khan
2000);
and
increased
alcohol
intake
(Donato
1997;
Fattovitch
1997;
Poynard
1997;
Rudot-Thoraval
1997;
Neiderau
1998;
Wiley
1998)
have
been
documented
by
many
(but
not
all)
as
highly
prognostic
factors
for
HCV-related
liver
disease
progression.
However,
other
important
prognostic
factors
for
advanced
disease
progression
have
been
less
consistently
documented
in
published
natural
history
studies.
Mode
of
HCV
transmission:
Blood
transfusion
vs.
IVDU
vs.
Sporadic
Cases.
Two
published
studies
have
suggested
that
infection
through
blood
transfusion
(BT)
(compared
to
infection
via
IVDU)
is a
highly
significant
prognostic
factor
for
liver
disease
progression
(Rudot-Thoraval
1997;
Gordon
1998).
Gordon
and
colleagues
studied
the
clinical
course
of
627
chronically
HCV-infected
patients:
282
(45%)
were
BT
recipients,
262
(42%)
were
infected
via
IVDU,
and
83
(13%)
were
without
known
risk
factors.
The
median
estimated
disease
duration
for
all
patients
was
21
years
(+/-
9.53
years)
and
the
duration
of
follow-up
ranged
from
1 to
25
years.
Liver
histology
was
available
on
463
patients.
Cirrhosis
was
determined
in
173/463
(37%):
118/173
(68%)
were
BT
recipients;
40/173
(23%)
were
infected
via
IVDU
(P<0.001).
Below
is a
breakdown
of
those
who
had
HCC,
cirrhosis,
or
no
cirrhosis:
Unlike
the
Poynard
study
(discussed
above),
in
Gordon's
patients,
age
or
estimated
disease
duration
did
not
predict
risk
of
liver
failure
in
the
multivariate
analysis
(Poynard
1997;
Gordon
1998).
Rudot-Thoraval
and
colleagues
from
France
also
noted
an
increased
prevalence
of
cirrhosis
in
BT
patients
in
their
survey
of
6,664
chronic
HCV
patients
(Rudot-Thoraval
1997).
Of
2,500
patients
with
known
duration
of
HCV
infection,
the
prevalence
of
cirrhosis
for
BT
recipients
was
22.8%
compared
to
5.8%
for
those
infected
via
IVDU
(P<0.02;
OR =
0.61;
95%
CI,
0.40-0.92).
"Sporadic
cases"
are
HCV
infections
without
identified
risk
factors.
Fattovitch
and
colleagues
from
Italy
noted
that
sporadic
cases
with
compensated
cirrhosis
had
poorer
survival
compared
with
those
infected
via
BT
or
IVDU
(Fattovitch
1997).
Likewise,
Khan
and
colleagues
from
Australia
recently
reported
that
sporadic
cases
were
at
significantly
higher
risk
for
cirrhosis,
HCC,
and
liver
transplantation
or
death
(Khan
2000).
The
complete
opposite
was
seen
in a
German
HCV
natural
history
study
conducted
by
Hopf
and
colleagues
(Hopf
1990).
Finally,
Poynard
did
not
find
any
of
these
modes
of
transmission
to
be a
significant
prognostic
factor
in
his
study
(Poynard
1997).
Abnormalities
in
Laboratory
Values:
Albumin
and
Bilirubin
In
the
455
Australian
HCV
patients
from
the
Khan
study,
serum
albumin
(a
protein
made
by
the
liver
that
is
responsible
for
maintaining
fluid
inside
blood
vessels)
concentrations
of
<30
g/L
at
entry
was
associated
with
an
85%
chance
of
liver-related
complications
at
five
years
and
a
three-year
mortality
of
70%
(Khan
2000).
Gordon
also
noted
that
low
serum
albumin
(3.2
g/L
compared
to
4.2
g/L)
was
an
independent
predictor
of
subsequent
hepatic
decompensation
(P =
0.001;
OR =
0.054;
95%
CI,
0.030-0.099)
(Gordon
1998).
Similar
findings
were
noted
years
earlier
in
two
HCV
natural
history
studies
conducted
by
Fattovich
and
colleagues
and
Yano
and
colleagues
(Yano
1996;
Fattovich
1997).
The
deleterious
effects
resulting
from
low
serum
albumin
levels
in
late-stage
HCV
patients
prompted
Hirsch
and
Wright
to
write
in a
Hepatology
editorial:
End-stage disease from hepatitis C is one of the leading indications for liver transplantation in the United States. Currently, listing for transplantation requires significant abnormalities in at least 2 of 5 elements of the Child-Pugh [cirrhosis] classification. This may merit reassessment if the dramatic predictive value of the serum albumin alone can be validated in other large, prospective studies. (Hirsch 2000)
To a
lesser
extent,
elevated
bilirubin
has
been
noted
as a
risk
factor
for
HCV-related
liver
disease
progression
(Fattovitch
1997;
Khan
2000).
In
their
1997
study
of
384
Italians
with
cirrhosis,
Fattovich
and
colleagues
found
that
abnormally
high
bilirubin
was
a
predictor
of
poorer
survival
(Fattovitch
1997).
Those
with
bilirubin
<17
mmo/L
had
five-
and
ten-year
survival
probabilities
of
96%
and
86%
respectively,
compared
with
81%
and
67%
for
those
with
bilirubin
>17-<51
mmo/L
(P =
0.0001).
Prolonged
prothrombin
time
(decreased
duration
of
blood
coagulation)
and
decreased
platelet
count
have
been
documented
as
significant
predictors
of
disease
progression
in
later-stage
patients
(Fatovitch
1997;
Gordon
1998).
Coinfection
with
HAV,
HBV,
and
HIV
(See
"Hepatitis
&
HIV
Coinfection"
chapter
for
more
details)
HCV
patients
who
acquire
HAV
have
been
found
to
have
a
substantial
risk
for
fulminant
hepatic
failure2
and
death
(Vento
1998).
In
an
Italian
HCV
natural
history
study,
432
patients
were
tested
thrice
yearly
for
the
development
of
HAV
antibodies.
Seventeen
HCV
patients
(three
with
cirrhosis)
subsequently
acquired
HAV
infection.
Ten
of
the
patients
had
an
uncomplicated
course
of
HAV,
but
seven
developed
fulminant
hepatic
failure,
and
six
died.
There
was
no
apparent
difference
in
degree
of
baseline
liver
damage,
yet
the
development
of
HAV
posed
a
41%
chance
of
fulminant
hepatitis
and
a
35%
chance
of
death
(Vento
1998).
Vento
concludes
that
all
HCV-infected
individuals
should
be
vaccinated
for
HAV,
saying,
"Chronic
carriers
of
HCV
who
are
at
risk
for
HAV
infection
should
be
vaccinated
against
HAV,
since
superinfection
with
this
virus
may
place
them
at
risk
for
severe,
life-threatening
acute
liver
damage"
(Vento
1998).
In a
subsequent
Lancet
editorial,
Marina
Berenguer
and
Teresa
Wright
agree
that
HAV
vaccination
may
be
warranted,
but
believe
that
Vento's
results
need
confirmation
and
that
a
cost-benefit
analysis
is
essential
before
implementing
such
a
policy
worldwide
(Berenguer
1998).
HCV
patients
with
HBV
have
been
found
to
have
an
increased
risk
for
cirrhosis
(Roudot-Thoraval
1997;
Cacciola
1999).
Cacciola
and
colleagues
from
Italy
tested
for
the
presence
of
HBV
DNA
in a
cohort
of
200
chronically
HCV-infected
individuals.
Sixty-six
(33%)
were
found
to
have
HBV
sequences.
Of
these
66
patients,
22
(33%)
had
evidence
of
cirrhosis
compared
to
26
(19%)
of
134
HCV-positive/HBV-negative
patients
(P =
0.04).
This
study
confirmed
the
results
of a
French
study
of
5,786
histologically
HCV-diagnosed
patients
(Roudot-Thoraval
1997).
Cirrhosis
at
liver
biopsy
was
found
in
24.6%
of
patients
positive
for
HBV
surface
antigens
compared
to
21.1%
in
those
who
were
HBV-antigen-negative
(P<0.001;
OR =
1.99;
95%
CI,
1.40-2.82).
Studies
of
people
coinfected
with
HCV
and
HIV
have
reported
that,
while
the
progression
of
HIV
disease
is
not
changed
by
HCV,
HCV
infection
progresses
more
rapidly
in
people
with
HIV.
When
matched
for
other
variables,
on
average,
people
who
are
HIV-positive
have
higher
levels
of
HCV
RNA
than
HIV-negative
people
(Eyster
1993,
1994;
Cribier
1995).
It
is
important
to
note
that
a
majority
of
natural
history
coinfection
studies
were
conducted
before
the
advent
and
widespread
use
of
potent
antiretroviral
therapy.
With
control
of
HIV
viremia
and
better
immune
status,
the
natural
history
of
HCV
in
these
patients
will
likely
change.
In
immunocompetent
HIV-positive
individuals,
HCV
may
replace
certain
opportunistic
infections
(i.e.,
Pneumocystis
carinii
pneumonia,
mycobacterium
avium
complex
and
cytomegalovirus
retinitis)
as a
leading
cause
of
increased
morbidity
and
mortality.
Benhamou
and
colleagues
from
Theiry
Poynard's
group
in
France
have
recently
reported
on
fibrosis
progression
in
their
well-characterized
coinfected
DOSVIRC
cohort
(Benhamou
1999a,
1999b).
Low
CD4
count
(<200
cells/mm3),
alcohol
consumption
of
more
than
50
grams/day,
and
age
at
HCV
infection
(>25
years
old)
were
shown
to
be
associated
with
an
increased
liver
fibrosis
progression
rate
(Benhamou
1999b).
In a
linear
progression
model,
there
was
little
difference
in
time
from
infection
to
cirrhosis
between
the
HCV+/HIV+
patients
and
the
matched
HCV+/HIV-
groups
if
those
with
coinfection
who
had
a
T-cell
count
of
>200
and
drank
<50
grams/day
of
alcohol.
The
accompanying
chart
documents
time
to
cirrhosis:
Virologic
Determinants
Quantitative
HCV
RNA
levels
do
not
appear
to
affect
the
clinical
course
of
HCV-infected
individuals
who
are
naive
to
treatment.
Lau
and
colleagues
found
no
difference
in
serum
HCV
RNA
levels
between
patients
with
chronic
persistent
hepatitis,
chronic
active
hepatitis,
or
cirrhosis
(Lau
1993).
These
finding
were
confirmed
in
larger
natural
history
studies
(Poynard
1997;
DeMoliner
1998).
There
is
considerable
debate
as
to
whether
certain
HCV
genotypes,
especially
1b,
put
patients
at
increased
risk
for
disease
progression.
Kabayashi
and
colleagues
found
that
the
deterioration
of
liver
histology
during
a
median
9.6
years
of
follow-up
was
more
common
in
patients
with
genotype
1
(68%)
--
namely
1b
--
than
in
those
with
genotype
2
(41.7%)
(P<0.01)
(Kobayashi
1996).
Likewise,
an
advanced
stage
of
liver
histology
was
more
common
in
the
genotype
1
patients
(63%)
compared
to
those
with
genotype
2
(38.9%)
(P<0.05).
An
earlier,
smaller
study
conducted
in
the
United
Kingdom
also
noted
that
those
with
genotype
1
had
a
far
more
progressive
histologic
disease
than
those
with
genotypes
2,
3,
or 4
(Dusheiko
1994).
However,
difference
in
disease
outcome
according
to
genotype
has
not
been
verified
in
most
treatment-naive
natural
history
studies
after
1996
(Poynard
1997;
Serfaty
1997;
Neiderau
1998;
Khan
2000).
Finally,
in
interviews
conducted
with
leading
hepatology
researchers
and
clinicians,
none
believe
that
genotype
independently
has
an
effect
on
the
natural
history
of
hepatitis
in
patients
naive
to
therapy
(see
"Current
Opinions
and
Controversies"
chapter).
- The METAVIR scoring system grades the stage of fibrosis on a five point scale: 0 = no fibrosis; 1 = portal fibrosis without septa; 2 = few septa; 3 = numerous septa without cirrhosis; 4 = cirrhosis (The METAVIR Cooperative Group 1994). Histologic activity (intensity of necroinflammatory lesion) is graded on a four point scale: A0 = no histologic activity; A1 = mild activity; A2 = moderate activity; A3= severe activity.
- Fulminant hepatic failure is the development of severe liver injury with hepatic encephalopathy (HE). HE is a condition where the brain function is impaired by the presence of toxic substances, absorbed from the colon, which are normally removed and detoxified by the liver.
References
Aach
RD,
Stevens
CE,
Hollinger
FB,
et
al.
Hepatitis
C
virus
infection
in
post-transfusion
hepatitis:
an
analysis
with
first-
and
second-generation
assays.
N
Engl
J
Med
325:1325-9,
1991.
Alter
HJ,
Conry-Cantilena
C,
Melpolder
J,
et
al.
Hepatitis
C
in
asymptomatic
blood
donors.
Hepatology
Sep:26(3
Suppl
1):29S-33S,
1997.
Alter
MJ,
Margoliis
HS,
Krawczynksi
K,
et
al.
The
natural
history
of
community-acquired
hepatitis
C
in
the
United
States.
N
Engl
J
Med
327:1899-905,
1992.
Benhamou
Y,
Bochet
M,
Dimartino
V,
et
al.
Anti-Protease
Inhibitor
Therapy
Decreases
The
Liver
Fibrosis
Progression
Rate
In
HIV-HCV
Coinfected
Patients
[abstract].
Hepatology
30:362A,
1999.
Benhamou
Y,
Bochet
M,
DiMartino
V,
et
al.
Liver
Fibrosis
Progression
in
Human
Immunodeficiency
Virus
and
Hepatitis
C
Virus
Coinfected
Patients.
Hepatology
30:1054-58,
1999.
Benvegnu
L,
Pontisso
P,
Cavalletto
D,
et
al.
Lack
of
correlation
between
hepatitis
C
virus
genotypes
and
clinical
course
of
hepatitis
C
virus-related
cirrhosis.
Hepatology
25:
211-15,
1997.
Berenguer
A,
Wright
TL.
Are
HCV-infected
individuals
candidates
for
hepatitis
A
vaccine
[editorial]?
Lancet
351:924-25,
1998
Cacciola
I,
Pollicino
T,
Squadrito
G,
et
a.
Occult
hepatitis
B
virus
infection
in
patients
with
chronic
hepatitis
C
liver
disease.
N
Engl
J
Med
341:22-6,
1999.
De
Moliner
L,
Pontisso
P,
De
Salvo
G L,
et
sl.
Serum
and
liver
HCV
RNA
levels
in
patients
with
chronic
hepatitis
C:
correlation
with
clinical
and
histological
features.
Gut
42:
856-860,
1998.
Deuffic
S,
Buffat
L,
Poynard
T,
et
al.
Modeling
the
hepatitis
C
virus
epidemic
in
France.
Hepatology
29:1596-601,
2000.
Di
Biscelie
AM,
Roggendorf
M,
Durkop
L,
et
al.
Long-term
clinical
and
histopatological
follow-up
chronic
posttansfusion
hepatitis.
Hepatology
14:969-74,
1991.
Di
Bisceglie
AM.
Natural
history
of
hepatitis
C:
its
impact
on
clinical
management.
Hepatology
31:1014-
18,
2000.
Dienstag
JL.
Non-A,
non-B
hepatitis.
I:
recognition,
epidemiology,
and
clinical
featurs.
Gastroenterology
85:439-62,
1983.
Dienstag
JL.
The
natural
history
of
chronic
hepatitis
C
and
what
should
we
do
about
it?
Gastroenterology
112:651-5,
1997.
Donato
F,
Tagger
A,
Chiesa
R,
et
al.
Hepatitis
B
and
C
virus
infection,
alcohol
drinking
and
hepatocellular
carcinoma:
a
case-control
study
in
Italy.
Hepatology
26:579-584,
1997.
Dusheiko
G,
Weiss
HS,
Brown,
et
al.
Hepatitis
C
virus
genotypes:
an
investigation
of
type-specific
differences
in
geographic
origin
and
disease.
Hepatology
19:13-18,
1994.
Esteban
JI,
Gonzalez
A,
Hernandez
JM,
et
al.
Evaluation
of
antibodies
to
hepatitis
C
virus
in a
study
of
transfussion-associated
hepatitis.
N
Engl
J
Med
323:1107-12,
1990.
Esteban
JI,
Cordoba
J,
Saulead
S.
The
picture
of
acute
and
chronic
hepatitis
C.
In
Reesink
HW,
ed.
Hepatitis
C
Virus.
Current
Studies
in
Hematology
and
Blood
Transfusion.
Basel:
Karger,
102-118,
1998.
Esteban
JI.
Treatment
of
acute
hepatitis
C.
In
Arroyo
V,
ed.
Treatment
of
Liver
Disease.
Barcelona:
Masson,
279-86,
1999.
Farci
P,
Alter
HJ,
Wong
D,
et
al.
A
long-term
study
of
hepatitis
C
virus
replication
in
non-A,
non-B
hepatitis.
N
Engl
J
Med
325:98-104,
1991.
Farci
P,
Shimoda
A,
Coiana
A,
et
al.
The
outcome
of
acute
hepatitis
C
predicted
by
the
viral
evolution
of
the
viral
quasispecies.
Science
288:339-44,
2000.
Fattovitch
G,
Giustina
G,
Degos
F,
et
al.
Morbidity
and
mortality
in
compansated
cirrhosis
type
C:
a
retrospective
follow-up
study
of
384
patients.
Gastroenterology
112:463-472,
1997.
Gordon
SC,
Bayati
N,
Silverman
AL.
Clinical
outcome
of
hepatitis
C
as a
fucntion
of
mode
of
transmission.
Hepatology
28:562-7,
1998.
Hirsch
KR,
Wright
TL.
"Silent
killer"
or
benign
disease.
The
dilemma
of
hepatitis
C
virus
outcomes
[editorial].
Hepatology
31:536-37,
2000.
Hopf
U,
Moller
B,
Kuther
D,
et
al.
Long-term
follow-up
of
post-transfusion
and
sporatic
chronic
hepatitis
non-A,
non-B
and
frequency
of
circulating
antibodies
to
heaptitis
C
virus
(HCV).
J
Hepatol
10:69-76,
1990.
Kenny-Walsh
E.
Clinical
outcomes
after
hepatitis
C
infection
from
contaminated
anti-D
immune
globulin.
N
Engl
J
Med
340:1228-33,
1999.
Khan
MH,
Farrell
GC,
Byth
K,
et
al.
Which
patients
with
hepatitis
C
develop
liver
complication?
Hepatology
31:513-20,
2000.
Koretz
RL,
Abbey
H,
Coleman
E,
et
al.
Non-A,
non-B
post-transfusion
hepatitis.
Looking
back
in
the
second
decade.
Ann
Intern
Med
119:110-5,
1993.
Koretz
RL,
Brezina
M,
Polito
AJ,
et
al.
Non-A,
non-B
posttransfusion
hepatitis:
comparing
C
and
non-C
hepatitis.
Hepatology
17:361-5,
1993.
Lau
JYN,
Davis
G,
Kniffen
J,
et
al.
Significance
of
serum
hepatitis
C
virus
RNA
levels
in
chronic
hepatitis
C.
Lancet
341:1501-04,
1993.
Mattsson
L,
Weiland
O,
Glaumann
H.
Chronic
non-A,
non-B
hepatitis
developed
after
transfusions,
illicit
self-injections
or
sporadically.
Outcome
during
long-term
follow-up--a
comparison.
Liver
9:120-7,
1989.
Niederau
C,
Lange
S,
Heintges
T,
et
al.
Prognosis
of
chronic
hepatitis
C:
results
of a
large,
prospective
cohort
study.
Hepatology
28:1687-95,
1998.
Pastore
G,
Monno
L,
Santantonio
T,
et
al.
Monophasic
and
polyphasic
pattern
of
alanine
aminotransferase
in
acute
non-A,
non-B
hepatitis.
Clinical
and
prognostic
implications.
Hepatogastroenterology
32:155-8,
1985.
Poynard
T,
Bedossa
P,
Opolon
P.
Natual
history
of
liver
fibrosis
progression
in
patients
with
chronic
heaptitis
C.
Lancet
349:825-32,
1997.
Ray
SC,
Wang
YM,
Laeyendecker
O,
et
al.
Acute
hepatitis
C
virus
structural
gene
sequences
as
predictors
of
persistent
viremia:
hypervariable
region
1 as
a
decoy.
J
Virol
73:2938-46,
1999.
Roudot-Thoraval
F,
Bastie
A,
Pawlotsky
J-M,
et
al.
Epidemiological
factors
affecting
the
severity
of
hepatitis
C
virus-related
liver
disease:
a
French
survey
of
6,664
patients.
Hepatology
26:485-490,
1997.
Seefff
LB.
Natural
history
of
hepatitis
C.
Hepatology
26(3
Suppl
1):21S-28S,
1997.
Seeff
LB.
The
natural
history
of
hepatitis
C
-- A
quandary
[editorial].
Hepatology
28:1710-12,
1998.
Seeff
LB.
Natural
history
of
hepatitis
C.
In:
Liang
TJ,
moderator.
Pathogenesis,
natural
history,
treatment
and
prevention
of
hepatitis
C.
Ann
Intern
Med
132:299-300,
2000.
Seeff
LB,
Miller
R,
Rabkin
CS,
et
al.
45-year
follow-up
of
hepatitis
C
virus
infection
in
healthy
young
adults.
Ann
Intern
Med
132:105-11,
2000.
Serfaty
L,
Chazouilleres
O,
Poujol-Robert
A,
et
al.
Risk
factors
for
cirrhosis
in
patients
with
chronic
hepatitis
C
virus
infection:
results
of a
case-controlled
study.
Hepatology
26:776-779,
1997.
Shakil
AO,
Conry-Cantilena
C,
Alter
HJ,
et
al.
Volunteer
blood
donors
with
antibody
to
hepatitis
C
virus:
clinical,
biochemical,
virologic,
and
histologic
features.
Ann
Intern
Med
123:330-7,
1995.
Tong
MJ,
El-Farra
NS,
Reikes
AR,
et
al.
Clinical
outcomes
after
transfusion-associated
hepatitis
C.
N
Engl
J
Med
332:1463-66,
1995.
Tremolada
F,
Casarin
C,
Tagger
A,
et
al.
Antibody
to
hepatitis
C
virus
in
post-transfusion
hepatitis.
Ann
Intern
Med
114:277-81,
1991.
Tsai
SL,
Chen
YM,
Chen
MH,
et
al.
Hepatitis
C
virus
variants
circumventing
cytotoxic
T
lymphocyte
activity
as a
mechanism
of
chronicity.
Gastroenterology
115:954-65,
1998.
Vento
S,
Garofano
T,
Renzini
C,
et
al.
Fulminant
hepatitis
associated
with
hepatitis
A
vrus
superinfection
in
patients
with
chronic
hepatitis
C.
N
Engl
J
Med
338:286-90,
1998.
Villano
SA,
Vlahov
D,
Nelson
KE,
et
al.
Persistence
of
viremia
and
the
importance
of
long-term
follow-up
after
acute
hepatitis
C
infection.
Hepatology
29:908-14,
1999.
Wiley
TE,
McCarthy
M,
Breida
L,
et
al.
Impact
of
alcohol
on
histological
and
clinical
progression
on
hepatitis
C
infection.
Hepatology
28:805-09,
1998.
Yano
M,
Kumada
H,
Kage
M,
et
al.
The
long-term
pathological
evolution
of
hepatitis
C.
Hepatology
23:1334-40,
1996.
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