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The
NIH Consensus Conference on the
Management of Hepatitis C:
2002. Part
1
Introduction
Alan
Franciscus
Editor-in-Chief,
Hepatitis C Virus Advocate
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The
National Institutes of Health convened the second Management
of Hepatitis C Consensus Development
Conference
on June 10, 2002 in Bethesda, Maryland.
The first Management of Hepatitis C Consensus
Conference
was held in March 1997 that established the current approaches
that are utilized in the
management
and care of Hepatitis C Virus. The
statement that will be issued as a result of this meeting will
have far
reaching
affects and consequences to the management, care and treatment
of hepatitis C and is therefore of
extreme
importance to the community.
It
is clear that major breakthroughs in the management and care
of Hepatitis C Virus have taken place in the years since the
first
conference. Some
statements listed in the original consensus conference that
have changed include:
Ψ
. persistent infection develops in perhaps as
many as 85% of patients with acute hepatitis C.
We
now know that the true number of people that develop
chronic infection is more likely between 50-55%
with a higher rate of spontaneous recovery in some
groups.
Ψ
The only available treatment for Hepatitis C Virus was various forms
of interferon with the bulk of available evidence pertains to the alpha interferons (interferon
alpha). Current
Hepatitis C Virus medications include interferon,
combination of interferon and ribavirin, pegylated
interferon and pegylated interferon and ribavirin.
Ψ
Treatment success was measured by normalization of
biochemical markers
that is ALTs and with
elimination of hepatitis C by viral load.
Sustained virological response is the elimination of
Hepatitis C Virus and is
now the end point of treatment.
Ψ
The sensitivity on anti Hepatitis C Virus tests and viral load tests
were questioned at the first consensus conference.
Now these tests are considered very sensitive and
accurate.
Ψ
At that time fibrosis was believed to be irreversible.
We now know that dramatic reversal of fibrosis or
scarring takes place with the elimination of Hepatitis C Virus from
successful Hepatitis C Virus treatment and some reversal of fibrosis takes place even in people that do not clear
Hepatitis C Virus from treatment.
The
first consensus conference has had many detractors in the
medical field and the community.
First, people
with
persistently normal enzymes (ALTs) were excluded from
treatment except under investigational studies.
We
now know that approximately 20% of people with persistently
normal enzymes level have moderate to
severe
disease progression and treatment should be evaluated under
different criteria for these patients.
Secondly,
people who are
drinking significant amounts of alcohol or who are actively
using illicit drugs should
be
delayed until these habits are discontinued for at least 6
months. This
is the most controversial area that
will
be addressed at this conference with many advocates actively
lobbying for treatment decisions on a
case-by-case
basis based upon the opinion of the medical provider and
patient after extensive evaluation.
One
of the most commonly used drugs by IDUs is heroin. Treatment for heroin addiction, which has been
endorsed
by a previous consensus statement, is opiate agonist therapy
(methadone). However,
the vast
majority
of medical providers will not treat this population. In addition the majority of transplant centers will not
list
a patient on methadone maintenance.
The majority of cases of Hepatitis C Virus are linked to active
injection drug use
and
the current government guidelines recommend against treating
active injection drug users.
If methadone
maintenance,
the recommended treatment, is not widely accepted as a
concomitant therapy during treatment
for
Hepatitis C Virus then how do can we give hope to the largest population
infected with Hepatitis C Virus and explain this
inconsistency.
Please
note that there we no major revelations in todays
presentations, but the review of the data and
questions
posed will provide us with many recommendations for future
research.
The
following are the opening session summaries for the NIH
Consensus Conference on the Management of
Hepatitis
C: 2002.
The
Course and Outcome of Hepatitis C
Jay
H. Hoofnagle, M.D.
Hepatitis
C is caused by a small RNA virus that belongs to the family
flaviviridae and is the sole member of the
genus
hepacivirus. First identified in 1989, the hepatitis C virus (Hepatitis C Virus)
has a single-stranded RNA genome that
is
~ 9.6 kilobases in length and encodes a single, large
polyprotein of ~ 3000 amino acids. The Hepatitis C Virus
polyprotein
is cleaved post-translationally into multiple structural and
non-structural peptides: structural
components
consist of a nucleocapsid core [C] and two envelope
glycoproteins [E1 & E2] and the
non-structural
proteins are labeled NS2 through NS5. The specific functions
of the individual NS proteins have
not
been completely elucidated. NS3 has both helicase and protease
activities and the NS5 region contains the
RNA-dependent
RNA polymerase activity essential for RNA viral replication.
These enzymatic activities are
potential
targets for antiviral compounds. Hepatitis C Virus RNA also has important
and highly conserved 5 and 3
untranslated
regions (UTRs). The 5 UTR has an internal ribosomal entry
site (IRES) essential for initiation of
viral
protein translation and the 3 UTR has structured RNA
elements essential for both viral replication and
translation.
There
are neither robust cell culture systems for propagation of Hepatitis C Virus
nor simple small animal models of the
infection,
so the replicative cycle of the virus has largely been deduced
from that of other flaviviruses. Hepatitis C Virus
replicates
in the cytoplasm of hepatocytes where it is not directly
cytopathic. Persistent infection appears to rely
upon
rapid production of virus and continuous cell-to-cell spread
along with a lack of vigorous T cell immune
response
to Hepatitis C Virus antigens. The Hepatitis C Virus RNA genome mutates frequently and
circulates in serum not as a single
species
but as a population of quasispecies with individual viral
genomes differing by 1 to 5 percent in
nucleotide
sequence. Six major genotypes (1 to 6) and more than 50
subtypes (e.g.,1a, 1b, 2a, 2b) have been
described.
Different isolates of Hepatitis C Virus differ by 515 percent, subtypes
by 1030 percent, and genotypes by as
much
as 3050 percent in nucleotide sequence.
Hepatitis
C can cause both acute and chronic hepatitis. Knowledge of the
course and outcome of infection
arises
largely from studies in chimpanzees and previous
post-transfusion and more current post-needlestick
accident
cases of hepatitis C. In acute hepatitis, Hepatitis C Virus RNA can be
detected in the serum within one to two
weeks
after exposure, rising thereafter to levels of 10 5 to 10 7
viral genomes per ml. Serum alanine
aminotransferase
(ALT) levels indicative of hepatocyte injury and necrosis
start to rise 2 to 8 weeks after
exposure
and usually reach levels of greater than 10 times the upper
limit of normal. About one-third of adults
with
acute Hepatitis C Virus infection develop clinical symptoms and jaundice,
the symptomatic onset ranging from 3 to 12
weeks
after exposure. In self-limited acute hepatitis C, symptoms
last for several weeks and subside as ALT
and
Hepatitis C Virus levels fall. Acute hepatitis C can be severe and prolonged
but is rarely fulminant. Antibody to Hepatitis C Virus as
detected
by enzyme immunoassay (EIA) arises at the time of or shortly
after onset of symptoms, so that 30
percent
of patients test negative for anti-Hepatitis C Virus at onset of symptoms,
making anti-Hepatitis C Virus testing unreliable in
diagnosis.
Almost all patients eventually develop anti-Hepatitis C Virus, although
titers can be low or even undetectable in
patients
with immune deficiencies.
Chronic
hepatitis C is marked by persistence of Hepatitis C Virus RNA for at least
six months after onset of infection. The
chronicity
rate of hepatitis C averages 7080 percent, but varies by
age, sex, race, and immune status. During
the
evolution of acute to chronic infection, Hepatitis C Virus RNA and ALT
levels can fluctuate markedly, some patients
having
periods during which Hepatitis C Virus RNA is undetectable and ALT levels
normal. Once chronic infection is
established,
however, serum Hepatitis C Virus RNA levels tend to be stable. Most patients
with chronic hepatitis C have few
if
any symptoms, the most common being fatigue, which is
typically intermittent. Right upper quadrant pain (liver
ache),
nausea, and poor appetite occur in some patients. Serum ALT
levels are usually continuously or
intermittently
elevated, but the height of elevations correlates poorly with
disease activity and at least one-third
of
infected persons have persistently normal ALT levels. In these
patients, the underlying disease is usually, but
not
always, mild and non-progressive. Liver histology in chronic
Hepatitis C Virus infection demonstrates chronic
mononuclear
cell infiltration in the parenchyma and portal areas, focal
hepatocyte necrosis, and variable
degrees
of fibrosis.
The
major long-term complications of chronic hepatitis C are
cirrhosis, end-stage liver disease, and
hepatocellular
carcinoma (HCC), which develop only in a proportion of
patients and only after many years or
decades
of infection. Progression to cirrhosis is often silent
clinically and some patients are not known to have
hepatitis
C until they present with the complications of end-stage liver
disease or HCC. Once cirrhosis is
present,
the ultimate prognosis is poor.
Other
complications of chronic hepatitis C can be important and
affect quality of life. The major extrahepatic
manifestations
of chronic Hepatitis C Virus infection are cryoglobulinemia,
glomerulonephritis, seronegative arthritis, sicca
syndrome,
and porphyria cutanea tarda. Hepatitis C Virus-related cryoglobulinemia is
the most common: up to 40 percent
of
patients with chronic hepatitis C may have low levels of
cryoglobulins in serum, but only 1 percent have
symptomatic
cryoglobulinemia with fatigue, arthralgias, skin rash, renal
disease, or neuropathy.
Thus,
the course of hepatitis C is variable, the severity of illness
ranging from a transient, self-limited and
asymptomatic
infection to a chronic, progressive liver disease that leads
ultimately to cirrhosis and HCC.
References
1.Lauer GM, Walker BD. Hepatitis C virus infection. N
Engl J Med 2001;345:4152.
2.Robertson B, Myers G, Howard C, et al.
Classification, nomenclature, and database development for
hepatitis C virus (Hepatitis C Virus)
and related viruses: proposals for standardization.
Arch Virol 1998;143:2393503.
3.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
1991;325:98104.
4.Alter MJ, Kniszon-Moran D, Nainan OV, et al. The
prevalence of hepatitis C virus infection in the United
States, 1988 through
1994. N Engl J Med 1999;341:55662.
5.Bellentani S, Tiribelli C. The spectrum of liver
disease in the general population: lesson from the Dionysos
study. J Hepatol
2001;35:5317.
--------------------------------------------------------------------------------
The
Burden of Hepatitis C in the United States
W.
Ray Kim, M.D., M.Sc., M.B.A.
Incidence
and Prevalence
Disease
frequency may be measured either by the pool of existing cases
(prevalence), or by the occurrence of
new
cases (incidence). The most widely quoted data on the
prevalence of Hepatitis C Virus in the United States are derived
from
the third National Health and Nutrition Examination Survey (NHANES),
a national survey of a
representative
sample of non-institutionalized civilian Americans conducted
between 1988 and 1994. Of
21,000
people tested for Hepatitis C Virus, 380 people (1.8 percent) carried
antibodies against the virus (anti-Hepatitis C Virus), of
whom
280 (74 percent) had detectable viral RNA in their serum.
These numbers project to 3.9 million
Americans
(95 percent confidence interval (CI): 3.14.8 million) who
have been infected with Hepatitis C Virus, of whom 2.7
million
(95 percent CI: 2.43.0 million) have ongoing chronic
infection. Hepatitis C is the most common chronic
blood-borne
infection in the United States.
While
Hepatitis C Virus is a reportable infectious disease in the United States,
the incidence of new Hepatitis C Virus infection is much
more
difficult to estimate than its prevalence. Since the majority
of acute Hepatitis C Virus infections are not accompanied
by
recognizable symptoms and thus not reported, enumerating
reported cases of acute hepatitis C significantly
underestimates
the true incidence of hepatitis C infection. Nonetheless, the
Centers for Disease Control and
Prevention
(CDC) estimate that the annual incidence of acute Hepatitis C Virus
infection in the United States decreased
from
an average of approximately 230,000 new cases per year in the
1980s to 38,000 cases per year in the
1990s.
It
may be expected that the reduction in new incident cases will
eventually lead to a decrease in the prevalence
of
Hepatitis C Virus. A report from CDC projected that, following a peak in the
mid-1990s at slightly above 2.0 percent, the
Hepatitis C Virus
prevalence would gradually decrease to 1.0 percent by 2030.
While the prevalence of Hepatitis C Virus infection may
be
decreasing, the prevalence of liver disease caused by Hepatitis C Virus is
on the rise. This is because there is a
significant
lag, often 20 years or longer, between the onset of infection
and clinical manifestation of liver
disease.
CDC projects a fourfold increase in the number of persons with
longstanding (20 years or longer)
infection
between 1990 and 2015. Furthermore, it is uncertain whether
the projected decline in the Hepatitis C Virus
prevalence
based on NHANES data (non-institutionalized civilians)
translates to other population groups known
to
have very high prevalence of Hepatitis C Virus. Examples of these groups
include patients at Veterans Affairs (VA)
hospitals,
active intravenous drug users, and prison inmates.
Mortality
from Hepatitis C Virus
Chronic
liver disease is one of the 10 most common causes of death in
the United States. There has been a
steady
increase in the number of deaths from liver disease over time.
The increase was mainly attributable to
viral
hepatitis and hepatic malignancies. On the other hand, the
age-adjusted death rate (deaths per 100,000
living
persons, adjusted to 2000 population census) from liver
disease has been relatively constant.
Mortality
statistics in the United States are based on the underlying
cause of death listed on death certificates.
As
deaths attributable to viral hepatitis primarily result from
chronic liver disease and liver failure and, in those
cases,
viral hepatitis may not necessarily be listed as the
underlying cause of death, it is likely that deaths
classified
as viral hepatitis underestimate the true incidence of deaths
related to viral hepatitis. Further, until
1999,
when the International Classification of Disease version 10
(ICD-10) began to be used to classify causes
of
death, Hepatitis C Virus was not given an independent code, making it
difficult to estimate the total number of deaths
attributable
to Hepatitis C Virus.
With
these caveats in mind, there was a sixfold increase in the
number of deaths from viral hepatitis (all types)
between
1982 (n=814) and 1999 (n=4853). In 1999, the first year Hepatitis C Virus
was reported separately, the majority
(77
percent, n=3759) of deaths from viral hepatitis were due to
Hepatitis C Virus. During the same period, there was a
commensurate
increase in the age-adjusted death rate from 0.4 to 1.8 deaths
per 100,000 persons per year.
To
estimate the degree of under-reporting of Hepatitis C Virus as the
underlying cause of death in the mortality data, the
number
of in-hospital deaths from liver disease related to hepatitis
C was enumerated (see below for details).
In
1998, there were an estimated 4500 in-hospital deaths in the
United States for liver disease related to Hepatitis C Virus
(source:
Healthcare Utilization Project, AHRQ).
Morbidity
and Health Care Cost from Hepatitis C Virus
As
chronic hepatitis C has a prolonged natural history and it is
only a relative minority of the infected that require
ongoing
medical care for their hepatitis, it is difficult to estimate
the magnitude of morbidity at the population
level.
A cost-of-illness study conducted by the American
Gastroenterological Association estimated that there
were
317,000 outpatient visits for the treatment of hepatitis C in
the United States in 1998. The cost for
outpatient
physician services was projected to be $23.9 million. During
the same year, $530 million was spent
for
antiviral treatment of Hepatitis C Virus.
Patients
with more advanced stage liver disease present with portal
hypertension and hepatic
decompensation,
as manifested by ascites, hepatic encephalopathy, or
gastrointestinal bleeding, which often
necessitates
inpatient care, including liver transplantation. End-stage
liver disease and/or hepatocellular
carcinoma
related to Hepatitis C Virus is already the most common indication for liver
transplantation in the United States.
In
1999, approximately one-third of available cadaveric livers
were transplanted into recipients with Hepatitis C Virus
infection.
The
nationwide impact of liver disease due to Hepatitis C Virus has been
estimated based on data derived from the
Nationwide
Inpatient Sample of the Healthcare Utilization Project. This
database represents a 20 percent
stratified
sample from all non-Federal, acute-care hospitals, which
account for approximately 95 percent of all
hospitalizations
in the nation. As liver disease from Hepatitis C Virus may not be the main
reason for all hospitalizations with
a
Hepatitis C Virus diagnosis, hospitalizations were divided into three
groups. These included hospitalizations in which liver
disease
from hepatitis C was the primary reason for hospitalization,
those in which liver disease from Hepatitis C Virus was
a
secondary reason, and those in which Hepatitis C Virus was an incidental
notation. Because of the uncertainty of
ascertainment
of Hepatitis C Virus in the early 90s, hospitalizations for other chronic
hepatitis (non-A, non-B) were also
captured.
There
was an almost fourfold increase during the five-year period
between 1993 (n=35,700) and 1998
(n=134,200)
in the total number of hospitalizations in which Hepatitis C Virus was
mentioned in the discharge diagnosis.
Some
of the increase was due to lack of ascertainment of Hepatitis C Virus in the
early 1990s, as there was a partially
corresponding
decrease in the non-A, non-B hepatitis hospitalizations (from
69,600 in 1993 to 47,800 in 1998).
The
number of hospitalizations in which liver disease was the
principal diagnosis increased from 10,100 to
32,800
and secondary diagnosis from 6,000 to 27,100 between 1993 and
1998. As expected, the increase in
hospital
services for Hepatitis C Virus-related morbidity was accompanied by a
similar increase in hospital charges.
Hospitalizations
were given differential weight depending on the relevance of
hepatitis C (principal diagnosis vs.
incidental notation). After adjustment for inflation (1998
US$), the total hospital charges for 1998 were
slightly
over 1 billion dollars nationwide. This represents doubling in
three years ($528M for 1995) and tripling in
five
years ($348M for 1993).
Summary
Hepatitis
C infection is common, affecting nearly 2 percent of the
general population and a much higher
percentage
of people under special circumstances. Since the early 1990s,
national statistics indicate that
morbidity,
mortality, and health care utilization associated with
consequences of long-standing infection with
hepatitis
C are increasing in epidemic proportions. Future projection
studies predict that the increase will
continue
in the foreseeable future.
References
1.Alter MJ, Kruszon-Moran D, Nainan OV, et al. The
prevalence of hepatitis C virus infection in the United
States, 1988 through
1994. New Eng J of Med, 1999:341(8):55662.
2.Anonymous. Recommendations for prevention and control
of hepatitis C virus infection and Hepatitis C Virus-related chronic
disease.
MMWR 1998, Centers for Disease Control and Prevention (CDC):
Atlanta, GA. 19.
3.Armstrong GL, Alter MJ, McQuillan GM, Margolis HS.
The past incidence of hepatitis C virus infection:
implications for the
future burden of chronic liver disease in the United
States. Hepatology 2000;31(3):77782.
4.Anonymous. Compressed mortality file <http://wonder.cdc.gov>.
2002 (accessed on 3/10), Centers for Disease Control and
Prevention.
5.Anonymous. The burden of gastrointestinal diseases.
2001, The American Gastroenterological Association: Bethesda,
MD.
4160.
6.Kim W, Gross J, Poterucha J, Locke G, Dickson E.
Outcome of hospital care of liver disease associated with
hepatitis C in
the United States. Hepatology 2001;33:2016.
------------------------------------------------------------------------
Natural
History of Chronic Hepatitis C
Leonard
B. Seeff, M.D.
Introduction
The
rationale for establishing the natural history of any disease
is to inform both the patient and physician of
future
expectations and to assess the need for treatment.
Unfortunately, the characteristics of hepatitis Cits
silent
onset, evolution to a generally asymptomatic and greatly
prolonged chronic phase, its co-mingling with
other
morbid conditions, and the fact that treatment that alters the
course is now almost routinehave limited
the
ability to accurately define its natural history. Several
strategies have been used for this purpose, all of which
have
their drawbacks but still have provided useful information.
Because of the many inherent difficulties, there
is
much controversy regarding the natural history of hepatitis C.
The outcome of concern is increasing fibrosis
progression,
culminating in cirrhosis and, occasionally, advancement to
hepatocellular carcinoma (HCC).
Some
believe this sequence to be common; others believe that
serious progression is relatively limited. Both of
these
views may be valid, both identifying a frequency of
progression that is modified by differing demographic
characteristics
of the population studied and by varying intrinsic and
extrinsic factors. In essence, the
controversy
derives from the uncertainty of whether or not fibrosis
progression is linear.
Advancement
from Acute to Chronic Hepatitis
The
natural history is a product of the outcome of the acute
infection as well as the outcome of the subsequent
chronic
hepatitis. A problematic issue is the actual timing of
evolution to chronic hepatitis. Traditionally, this has
been
based on persistence of virus for at least 6 months. However,
viremia may persist beyond this time,
although
it is believed that loss of virus after one year is
exceptional. Prospective study has indicated that
chronic
hepatitis evolves in about 85 percent of acutely infected
persons. On the other hand, cross-sectional
studies
of large, untreated anti-Hepatitis C Virus positive cohorts, consisting
mainly of young persons, many of them female,
have
reported absent virus in as many as 4550 percent of
instances, implying a higher rate of spontaneous
recovery
in some groups. Thus, spontaneous recovery from acute
hepatitis C occurs in 1545 percent of
instances.
Progression
to Cirrhosis
Once
chronic hepatitis has developed, the question then is: What
are the long-term sequelae? Numerous
efforts
have been made to define the frequency and rate of progression
to cirrhosis and HCC. Evident in all
these
studies is that clinically overt liver disease is generally
not seen in the first two decades following the
acute
infection. This does not imply that cirrhosis does not evolve
during this period, but the actual timing of its
onset
cannot be determined without performing serial liver biopsies.
Early reports, based largely on
retrospective
studies, indicated that, at the end of two decades of
infection, about 20 percent had developed
cirrhosis,
although some of the studies have reported rates of almost 50
percent. The drawbacks of
retrospective
studies are that evaluation is limited to those who have
achieved an end point and that tracing to
disease
onset is hindered by the paucity of symptoms at onset. Thus,
ascertainment bias may exist using this
approach.
Later prospective studies, mainly of Hepatitis C Virus-infected transfusion
recipients, reported a lower rate of
development
of cirrhosis (716 percent), but most of these studies were
too short in duration to provide an
accurate
assessment of the ultimate outcome. Even lower rates of
cirrhosis have been reported among several
groups
in whom it was possible to trace back far in the past to the
time of onset or near onset. Thus, among
children
infected through transfusion in the first years of life and
traced 20 years later, and among young women
infected
through receipt of Hepatitis C Virus-contaminated Rh immunoglobulin and
traced over approximately the same
time
period, cirrhosis was noted to have occurred in about 2
percent. A similar rate was noted in a 45-year
follow
up of young Hepatitis C Virus-positive military recruits who had been bled
at the time of serving on a military base, the
samples
having been retained in a repository. The common theme of this
lower rate of cirrhosis is that it was
noted
among persons infected at a young age.
Taking
the numerous variety of studies into account, a group of
Australian investigators who reviewed the
worlds
literature for the rate of cirrhosis development at 20 years
concluded that the studies could be divided
into
4 broad categories: those performed in liver clinics, the mean
cirrhosis rate being 22 percent (95 percent
CI,
1826 percent); post-transfusion hepatitis studies, with a
mean of 24 percent (1137 percent); studies of
blood
donors, with a mean of 4 percent (17 percent); and studies
of community-based cohorts, with a mean of
7
percent (410 percent). They concluded that selection bias
accounted for the two higher rates, and that the
community-based
cohort studies appeared more representative in estimating
disease progression at a
population
level. These data provide useful figures for the frequency of
progression to cirrhosis two decades
after
acute infection that appears to range between about 24
percent to 2025 percent, depending on several
factors,
to be described below. However, many of those infected are
young and are destined to live for several
more
decades. Therefore the question that must be posed is: What
happens after the first two decades with
regard
to liver disease progression? Does fibrosis progression
continue to increase at a linear rate? Does the
rate
level off and remain the same throughout life? Does fibrosis
progression increase as age advances?
Certainly,
many chronically infected persons are known to live for a
lifetime without succumbing to liver disease,
whereas
others are known to develop end-stage liver disease 30 to 60
years after acute infection. Thus, these
questions
can only be answered by conducting markedly extended studies,
few of which have been
accomplished
for obvious reasons. Other approaches have been to model the
expected outcome based on
preconceived
notions, models that may or may not turn out to be valid. Most
important, is it possible to predict
in
the individual Hepatitis C Virus-infected person what the outcome is likely
to be? The answer is a qualified maybe, taking
into
account the many factors that might enhance progression.
Factors
That May Determine Progression
The
differing outcomes suggest that there are variables that may
contribute to the rate of liver disease
progression.
These can be considered as being viral-related, host-related,
or a consequence of external factors.
Viral-Related
Factors
that might contribute include viral load, viral genotype, and
quasispecies diversity. There is little
evidence
to indicate that viral load plays a role in disease
progression; there are suggestions that progression
is
more likely following infection with genotypes 1a and 1b than
genotype 2, although this has been disputed,
most
studies now reporting that there is no effect of genotype
characteristics on disease outcome. While the
degree
of quasispecies diversity appears to play a role in evolution
from acute to chronic hepatitis, there is no
evidence
that it enhances progression of already established chronic
hepatitis.
Host-Related
One
of the most important determinants is age at the time of
infection, the relationship being an inverse one.
What
is not yet established is whether the relatively mild disease
seen two decades after infection of young
people
will begin to accelerate with increasing age. This brings into
account the fact of duration of infection,
since
it is rare although not unheard of, to identify end-stage
liver disease in under one-and-a-half to two
decades.
Perhaps the flourishing of liver disease with time may be a
consequence in part of age-related
immune
depression. Certainly, an immune suppressed state vigorously
enhances disease progression as is
noted
among infected persons with hypogammaglobulinemia and,
especially, HIV co-infection. Hepatitis B and
schistosomal
co-infection also increase disease progression perhaps through
induced immune dysfunction as
well
as through direct cytotoxicity. Genetic background also may be
of importance. Genes of the major
histocompatability
complex appear also to play a role, not so much in
fibrogenesis, but in clearance of the virus.
HLA
class I antigens seem to be associated with viral persistence
whereas class II antigens (DRB1 alleles) are
identified
more frequently in those who clear virus and therefore have
milder disease. Inheritance of high TGF-β
1
and angiotensinogen-producing genotypes has been linked to
fibrosis progression. Co-morbid conditions
such
as hemochromatosis and non-alcoholic steatohepatitis are also
associated with advancing chronic liver
disease.
In addition, outcome may be influenced by gender and race.
Females are reported to have a slower
rate
of progression, a finding that seems to be emerging also among
African-Americans. Finally, the
expression
of the disease plays a role in outcome. Hepatitis C Virus-infected persons
with raised aminotransferase levels
are
far more likely to develop progressive liver disease than are
those with normal serum enzymes.
External
Factors
Clearly,
associated chronic alcoholism is a powerful co-factor in liver
disease progression. Yet to be
determined
is what is the least amount of alcohol and the type of
drinking pattern that plays a role in advancing
chronic
hepatitis C. Also of note are the data suggesting that smoking
may increase disease progression.
Exposure
to toxic products, either in the form of administered drugs
that may be hepatotoxic or as
environmental
contaminants, may have important effects. It is noteworthy
that death associated with chronic
hepatitis
C in the United States is more likely to be a result of
end-stage liver disease rather than HCC,
whereas
in Japan, virtually all deaths are attributed to HCC. It has
been suggested that the difference is a
consequence
of a longer duration of Hepatitis C Virus infection in Japan than in the
United States, a view that may or may
not
be valid. Another possible explanation is that toxic
environmental contaminants may play a contributory role
in
Japan.
Progression
From Cirrhosis to HCC
HCC
rarely (if ever) develops in persons with chronic hepatitis C
without preceding cirrhosis or significant
fibrosis.
The strongest evidence for a relationship between Hepatitis C Virus
infection and HCC comes from Japan, but
supporting
evidence comes from many other countries including the United
States, Italy, Spain, Egypt, France,
and
elsewhere. Recent evidence indicates that the incidence of HCC
increasing in the United States is
presumed
to be a consequence of the mushrooming of hepatitis C
infection in the 1960s and 1970s. The data
in
the United States indicate that once cirrhosis has developed,
HCC evolves at the rate of 14 percent per
year.
The figure in Japan is even higher.
References:
1.Alter HJ, Seeff LB. Recovery, persistence, and
sequelae in hepatitis C infection: a perspective on long-term
outcome. Semin
Liv Dis 2000;20:1735.
2.Poynard T, Bedossa P, Opolon P, for the OBSVIRC,
METAVIR, CLINIVIR, and DOSVIRC groups. Natural history of
liver fibrosis progression in patients with chronic hepatitis
C. Lancet 1997;349:82532.
3.Tong MJ, El-Farra NS, Reikes AR, Co RL. Clinical
outcomes after transfusion-associated hepatitis C. N Engl J
Med1995;332:14636.
4.Kenny-Walsh E for the Irish Hepatology Research
Group. Clinical outcomes after hepatitis infection from
contaminated
anti-globulin. N Engl J Med 1999;340:122833.
5.Vogt M, Lang T, Frosner, et al. Prevalence and
clinical outcome of hepatitis C infection in children who
underwent cardiac
surgery after implementation of blood-donor screening.
N Engl J Med 1999;341:86670.
6.Wiese M, Berr F, Lafrenz M, et al. Low frequency of
cirrhosis in a hepatitis C (genotype 1b) single-source
outbreak in
Germany: a 20-year multicenter study. Hepatology
2000;32:916.
7.Thomas DL, Astemborski J, Rai, et al. The natural
history of hepatitis C virus infection: host, viral, and
environmental factors.
JAMA 2000;284:4506.
8.Freeman AJ, Dore GJ, Law MG, et al. Estimating
progression to cirrhosis in chronic hepatitis C virus
infection. Hepatology
2001;34:80916.
9.Seeff LB, Hollinger FB, Alter HJ, et al. Long-term
mortality and morbidity of transfusion- associated non-A,
non-B and type C
hepatitis: a National Heart, Lung, and Blood Institute
collaborative study. Hepatology 2001;33:45563.
10.Seeff LB. Why is there such difficulty in defining
the natural history of hepatitis C? Transfusion
2000;40:11614.
--------------------------------------------------------------------------
Fibrosis
and Disease Progression
Patrick
Marcellin, M.D.
Chronic
infection with Hepatitis C Virus is associated with the typical histological
features of chronic hepatitis including
hepatocellular
necrosis and inflammation (activity or grade) and fibrosis
(stage). While the activity of the chronic
liver
disease can fluctuate over time, the stage of fibrosis is
believed to be progressive and largely irreversible.
In
chronic hepatitis C, the rate at which fibrosis progresses
varies markedly. In some individuals, fibrosis
ultimately
leads to cirrhosis, which is associated with the major
complications of the liver disease: portal
hypertension,
liver failure, and hepatocellular carcinoma. In others,
fibrosis does not appear to progress even
after
decades of infection. For these reasons, assessment of the
stage and rapidity of progression of fibrosis
can
be helpful in determining the prognosis and the need for
therapy in the individual patient. Factors
associated
with fibrosis progression are not well defined and the role of
necro inflammatory activity is still
controversial.
Assessment
of the Stage of Fibrosis
Liver
biopsy remains the gold standard to assess fibrosis. Several
systems for scoring liver fibrosis have been
proposed,
each based upon visual assessment of portal and periportal
fibrosis. The more frequently used
systems
are the Histology Activity Index (HAI: Knodell score), the
Ishak modification of the HAI score, and the
METAVIR.
The HAI scoring system ranges from 0 to 22 and fibrosis is
staged as 0, 1, 3, and 4. This
discontinous
scale was developed to allow for clear separation of mild (1+)
from extensive (3+) fibrosis which
has
important prognostic value. The HAI system is simple and has
been widely used, particularly in the large
multicenter
trials of interferon and ribavirin therapy of chronic
hepatitis C. However, the intra- and inter-observer
reproducibility
of the HAI is not very good and distinction between stages 1
and 3 may be difficult. In addition,
its
discontinous scale complicates statistical analysis in
clinical trials.
The
modification of the HAI scoring system proposed by Ishak et
al. is more sensitive in assessing fibrosis.
Fibrosis
stage is scored continuously from 0 to 6, which permits a
better assessment of the effect of therapy on
fibrosis.
The Ishak score is better validated and gives a more accurate
assessment of fibrosis.
The
METAVIR scoring system is simple; fibrosis stages are scored
continuously from 0 to 4. This system has
been
carefully validated in large groups of patients with chronic
hepatitis C and has shown good intra- and
inter-observer
reproducibility.
Important
limitations of these scoring systems should be emphasized.
Hepatic fibrosis may not be homogenous
throughout
the liver and the liver specimen obtained by needle biopsy may
not accurately reflect the overall
average
degree of fibrosis. The reliability of the assessment of
fibrosis stage increases with the size of the liver
sample.
In most studies, a minimum length of 10 mm is required.
Regardless of biopsy length, however, fibrosis
may
be underestimated and cirrhosis missed in some patients.
Factors
Associated With the Stage of Fibrosis
Most
cross-sectional studies of large numbers of liver biopsies
have shown that the stage of fibrosis is
associated
with patient age, the age at onset of infection, male sex, a
history of heavy alcohol consumption, and
the
presence of immune deficiency, such as HIV co-infection or
immunosuppressive therapy. The mechanisms
by
which age and sex affect the degree of fibrosis are not known.
Alcohol, which by itself can cause liver
disease
and fibrosis, may worsen fibrosis in hepatitis C at amounts
that are not injurious in non-infected
persons,
but the amount of alcohol beyond which the progression of
fibrosis is increased is unknown.
Serum
biochemical tests do not reliably predict the stage of
fibrosis. Currently available, indirect serum
markers
of fibrosis are not reliable, particularly in discriminating
between mild and moderate degrees of
fibrosis.
In cross-sectional studies, serum alanine and aspartate
aminotransferase (ALT and AST) levels do not
correlate
well with fibrosis. However, patients with documented,
persistently normal ALT levels usually have mild
degrees
of hepatitis and either no or mild stages of fibrosis. The
association between fibrosis stage and the
necroinflammatory
activity scores on liver biopsy is controversial.
Necroinflammatory activity is a dynamic
process
in chronic hepatitis C and may fluctuate over time. Therefore,
the activity score reflects the severity of
necrosis
and inflammation at a given point.
Factors
Associated With Progression of Fibrosis
From
retrospective studies and from some prospective studies done
in patients infected by blood transfusion at
a
relatively older age, it is estimated that 20 percent of
patients with chronic hepatitis C develop cirrhosis within
20
years of onset. In contrast, studies of cohorts of women who
did not drink alcohol and who were infected by
Rh
immune globulin at a young age indicated that fewer than 5
percent developed cirrhosis within 20 years. These
natural history studies validate the importance of age, sex,
and alcohol intake in progression of fibrosis.
Cross-sectional
studies using mathematical modeling performed on cohorts of
patients with a single liver
biopsy
suggest that the average rate of progression of fibrosis in
chronic hepatitis C is 0.133 METAVIR points
per
year. Based on this rate, the estimate is that cirrhosis
develops in the average patient after 30 years. The
average
delay to the development of cirrhosis ranges from 13 years in
infected men aged 40 or more years
who
drink more than 50 g of alcohol to 42 years in infected women
under 40 years of age who do not drink
alcohol.
Furthermore, the progression of fibrosis is probably not
linear. For instance, the time required to
progress
from stage 0 to 2 may be far longer than the time required to
progress from stage 3 to 4. Moreover,
fibrosis
progression may accelerate with age (particularly after the
age of 50). Finally, fibrosis may remain mild
and
stable for decades and may even regress spontaneously in some
patients.
The
progression of fibrosis is difficult to predict in the
individual patient particularly based upon assessment at
one
point in time. There are no good clinical, biochemical, or
virological tests that predict progression of
fibrosis.
High serum ALT levels have been associated with more active
liver disease and more rapid
progression
of fibrosis in some prospective studies, which supports the
use of monitoring of ALT levels in
assessing
prognosis and need for therapy. However, the validity of this
approach and the level above which the
ALT
elevations are predictive of more rapid progression is not
known. Virological factors such as serum Hepatitis C Virus
RNA
level and Hepatitis C Virus genotype are not predictive of fibrosis.
Genotype 3 is associated with more liver steatosis
than
other genotypes, and steatosis itself, as well as other
metabolic factors (such as lipid disorders, obesity,
insulin
resistance, and diabetes) may also predispose to more rapid
progression of fibrosis.
Repeat
liver biopsy is the only reliable means of assessing the
progression of fibrosis and is commonly
recommended
every 3 to 5 years in untreated patients. A second liver
biopsy can distinguish patients with
rapidly
progressive fibrosis, but may also merely indicate that the
initial biopsy underestimated the degree of
fibrosis.
Overall, the risk of progression of fibrosis of more than one
point in a 3 to 5 year period is low. In
patients
with factors associated with a higher risk of progression such
as age beyond 50 years, alcohol
consumption,
or high serum ALT levels, liver biopsy may be recommended more
frequently (2 to 3 years); in
contrast,
in the younger patient with no other risk factors, liver
biopsies may be performed less frequently (every
5
to 6 years).
References
1.Ishak K, Baptista A, Bianchi L, Callea F, De Groote
J, Gudat F, Denk H, et al. Histologic grading and staging of
chronic
hepatitis. J Hepatol 1995;22:6969.
2.Bedossa P, Poynard T. The METAVIR cooperative study
group. An algorithm for the grading of activity in chronic
hepatitis C.
Hepatology 1996;24:28993.
3.Tong MJ, El-Farra NS, Reijes AR, Co RL. Clinical
outcomes after transfusion-associated hepatitis C. N Engl J
Med 1995;
332:14636.
4.Poynard T, Bedossa P, Opolon P for the OBSVIRC,
METAVIR, CLINIVIR, and DOSVIRC groups. Natural history of
liver
fibrosis progression in patients with chronic hepatitis
C. Lancet 1997;349:82532.
5.Alter HJ, Seeff LB. Recovery, persistence, and
sequelae in hepatitis C virus infection: a perspective on
long-term outcome.
Sem Liver Dis 2000;20:1735.
--------------------------------------------------------------------------
Non-Invasive
Monitoring of Patients With Chronic Hepatitis C
Robert
J. Fontana, M.D., and Anna S.F. Lok, M.D.
Patients
with chronic hepatitis C (CHC) are at risk of developing
cirrhosis, liver failure, and hepatocellular
carcinoma
(HCC). However, specific symptoms and physical findings of
chronic liver disease are frequently
absent
until patients develop hepatic decompensation. Thus, clinical
examination is often unreliable in
assessing
the severity of liver disease in patients with CHC. Liver
histology is the gold standard for establishing
the
severity of liver injury and fibrosis, but this procedure is
associated with risks of complications, discomfort,
and
expense. In addition, sampling error may occur leading to
erroneous staging. Nonetheless, information on
the
extent of hepatic fibrosis or stage of liver disease is
important for prognostication as well as for decisions
on
treatment. As a result, practicing physicians are in need of
simple, safe, inexpensive, and reliable means to
non-invasively
assess the severity of liver disease in patients with CHC.
The
initial evaluation of patients with CHC should include a
thorough history and physical examination. A PCR
assay
for Hepatitis C Virus RNA is recommended to confirm the presence of viremia
because up to 30 percent of individuals
who test positive for Hepatitis C Virus antibody (anti-Hepatitis C Virus) may have
resolved infection or a false positive EIA
result.
Quantitative Hepatitis C Virus RNA levels and Hepatitis C Virus genotypes do not correlate
with disease severity, but these
results
are useful in predicting the likelihood of an antiviral
treatment response. The initial evaluation should
include
a comprehensive metabolic panel, prothrombin time, and
complete blood counts (CBC) with platelets.
Serum
aspartate and alanine aminotransferase (AST/ALT) levels
reflect liver injury, but the correlation with
histologic
necroinflammatory activity as well as the severity of hepatic
fibrosis is poor (1,2) . Serum albumin and
bilirubin
levels and prothrombin time reflect hepatic function, but
these values usually remain normal even in
patients
with compensated cirrhosis. Thus, routine blood tests cannot
differentiate early (minimal fibrosis) from
advanced
(compensated cirrhosis) stage of liver disease. Among the
routine blood tests, decreased platelet
count
is the earliest indicator of cirrhosis (3). Other
investigators have found that as patients progress from
chronic
viral hepatitis to cirrhosis, there is reversal of AST/ALT
ratio to >1. (4)
Ultrasound
is often recommended as part of the initial evaluation of
patients with CHC. Ultrasound and other
imaging
techniques such as CT and MRI can be used to diagnose
cirrhosis based on the presence of an
enlarged
spleen, small nodular liver, ascites, or varices. In addition,
these techniques may detect HCC.
However,
current imaging is unable to assess the extent of hepatic
fibrosis and to diagnose early cirrhosis.
Other
novel but less well-established non-invasive means of
assessing disease severity in patients with
compensated
CHC are under development. Serum fibrosis markers that reflect
the balance between
fibrogenesis
and fibrolysis have been proposed as a simple, non-invasive
means of assessing hepatic fibrosis.
(5,6)
To date, none of these markers alone correlates well with
hepatic fibrosis. Whether a panel of markers
such
as hyaluronic acid, YKL-40, and PIIINP will replace liver
biopsies remains to be determined. (7,8)
Contrast-enhanced
ultrasound doppler has also been proposed as a simple,
non-invasive means of detecting
advanced
hepatic fibrosis. (9) However, this method has not yet been
validated and will require sophisticated
instruments
and operators for optimal performance. Radionuclide liver
spleen scans can detect the presence of
portal
hypertension but are insensitive in the diagnosis of early
cirrhosis. Similarly, the use of various metabolic
probes
to assess functional liver mass has been reported to be
reliable in differentiating patients with
compensated
from decompensated liver disease, but these studies are
cumbersome and have not been
proven
to be useful in distinguishing patients with various stages of
hepatic fibrosis. (10)
The
optimal frequency and types of tests that should be performed
for monitoring CHC patients who are not on
antiviral
therapy have not been determined. In general, tests for CBC
and platelets and a comprehensive
metabolic
panel should be performed every six months. As discussed
above, a progressive decrease in
platelet
counts or a reversal of the AST/ALT ratio suggests the
development of cirrhosis. Repeat testing of
anti-Hepatitis C Virus,
Hepatitis C Virus RNA level, or Hepatitis C Virus genotype is unnecessary and does not
provide any information on the
stability
or progression of liver disease. For patients with known
cirrhosis, alfa fetoprotein testing and
ultrasound
should be included although the efficacy of these tests in HCC
surveillance is low. Upper endoscopy
should
be performed in patients with cirrhosis, especially those with
clinical evidence of portal hypertension, to
determine
the need for prophylaxis against variceal bleeding. Patients
with decompensated cirrhosis may need
more
frequent monitoring to determine the optimal timing for
transplant evaluation. Monitoring may be less
frequent
in patients with persistently normal aminotransferases and
those with minimal hepatic fibrosis after a
long
duration of infection (slow progressors). Because of the
variable natural course of CHC and the possibility
of
sampling error, many hepatologists recommend repeat liver
biopsies in 45 years in patients who decide not
to
receive antiviral treatment based on the finding of early
disease at initial evaluation. The availability of
non-invasive
tests that correlate with progression of hepatic fibrosis will
obviate the need for repeat liver
biopsies.
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