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Abstract and Introduction
Abstract
Estimates of the extent of hepatic fibrosis and the rate of fibrosis progression represent important surrogate end
points for evaluation of the vulnerability of an individual patient and for assessment of the impact of treatment on
natural history in chronic hepatitis C. Using the median fibrosis progression rate, the median expected time to
cirrhosis in untreated patients is around 30 years. However, one third of patients have an expected median time to
cirrhosis of less than 20 years and one third will only progress to cirrhosis in more than 50 years, if ever. Factors
independently associated with fibrosis progression are duration of infection, age, male gender, consumption of
alcohol, human immunodeficiency virus co-infection, and low CD4 count. Evaluation of fibrosis progression is
useful to decide treatment. Among patients with sustained viral response, fibrosis regresses. Evaluation of fibrosis
progression has permitted validation of the concept of suppressive therapy. Among patients without viral
clearance, interferon alone or in combination with ribavirin significantly reduces fibrosis progression rate in
comparison with progression before treatment and to control groups. There is a major need for noninvasive
markers of liver fibrosis. None are clearly useful today for the diagnosis of early stages of fibrosis. [Sem Liver
Disease 20(1):47-55,2000. 2000 Thieme Medical Publishers, Inc.]
Introduction
Worldwide, the major clinical consequence of chronic hepatitis C infection is the progression to cirrhosis and its
potential complications: hemorrhage, hepatic insufficiency, and primary liver cancer. Cumulative evidence strongly
suggests that the increase in mortality due to hepatocellular carcinoma in most Western countries is due to
hepatitis C infection.
Current understanding of hepatitis C virus (HCV) infection has been advanced by the concept of liver fibrosis
progression. Fibrosis is the deleterious but variable consequence of chronic inflammation. It is characterized by
the deposition of extracellular matrix components, leading to the distortion of the hepatic architecture with
impairment of liver microcirculation and liver cell function. HCV is usually only lethal when it leads to cirrhosis, the
last stage of liver fibrosis. Therefore, an estimate of fibrosis progression represents an important surrogate end
point for evaluation of the vulnerability of an individual patient and for assessment of the impact of treatment on
natural history.
For hepatologists, liver biopsy is considered to be an essential procedure for making rational decisions in patients
with chronic hepatitis C. For patients and general practitioners, it can be considered as an aggressive procedure.
The aim of this chapter is to review the different markers of liver fibrosis progression and to discuss the
appropriateness of liver biopsy in comparison with other procedures in chronic hepatitis C.
Fibrosis Stages and Necroinflammatory Activity Grades
Activity (necroinflammation) and fibrosis are two major histologic features of chronic hepatitis C included in
different proposed classifications. One of the few validated scoring systems is called the METAVIR scoring
system. This system assesses histologic lesions in chronic hepatitis C using two separate scores, one for
necroinflammatory grade (A for activity) and another for the stage of fibrosis (F). These scores are defined as
follows; stages of fibrosis (F) (Fig. 1): F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare
septa, F3, numerous septa without cirrhosis; F4, cirrhosis. Grade for activity (A): A0, no histologic
necroinflammatory activity; A1, minimal activity, A2, moderate activity, A3, severe activity. The degree of activity
Fibrosis in Patients with Hepatitis C: Detection and Significance:
Detection and Significance
Thierry Poynard, M.D., Ph.D., Vlad Ratziu, M.D., Yves Benmanov, M.D., Vincent Di Martino, M.D., Pierre Bedossa, M.D.,
Ph.D., Pierre Opolon, M.D.
Semin Liver Dis. 2000;20(1)
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was assessed by integration of the severity of the intensity of both piecemeal (periportal) necrosis and lobular
necrosis as described in a simple algorithm. The intra- and interobserver variations of this METAVIR scoring
system are lower than those of the widely used Knodell scoring system. For METAVIR fibrosis stages there is an
almost perfect concordance (kappa = 0.80) among pathologists.
As did others, we observed that fibrosis stage and inflammatory grade were correlated. However, for 36% of
patients, there was a discordance (178 of 500). If recommendations for treatment had been based on activity
grades, 56% of patients without significant activity (119 of 214) would not have been treated despite significant
fibrosis. In these patients who were infected for more than 10 years, fibrosis progression was therefore not related
to significant activity, which also raises questions concerning the pathophysiology of fibrosis. The other discordant
cases were 59 patients with nonsignificant fibrosis despite significant activity. This observation raises the question
of the utility of treatment of significant inflammatory damages if fibrosis does not occur. To summarize, clinicians
should not take "significant activity" as a surrogate marker of "severe disease." Fibrosis stage is the result of the
imbalance between synthesis and degradation of extracellular matrix components. Hepatic stellate cells are the
major cell types involved in extracellular matrix production (i.e., collagens, fibronectin, and laminin). Although
hepatic stellate cells produce extracellular matrix under the influence of various stimuli (growth factors, cytokines,
and lipid peroxydation products), they also produce a set of matrix metalloproteinases (MMPs) that control
degradation. MMPs are a family of related zinc-dependent endopeptidases capable of degrading all extracellular
matrix components, playing a major role in extracellular matrix remodeling. Finally, proteolytic activity of MMPs
can be inhibited by the tissue inhibitors of metalloproteinases, a group of proteins also produced by hepatic
stellate cells. Activity grade, which represents necrosis is not a good predictor of fibrosis progression. In fact,
fibrosis alone is the best marker of ongoing fibrogenesis. So far there is no study demonstrating clearly that
activity grades are predictive of fibrosis progression independently of fibrosis stage.
Fibrosis as a Time-Dependent End Point
Because fibrosis stage summarizes the vulnerability of a patient and is predictive of the progression to cirrhosis,
we looked at its association with the duration of infection and age at biopsy. The basic concept was to estimate
the transition times from infection to cirrhosis and between the different stages of fibrosis (Fig. 2). An ideal
assessment would have been to follow a large representative sample of patients prospectively from infection to
death, with repeated liver biopsies and without treatment. Obviously, this type of study is both ethically and
pragmatically impossible. The rare published studies on several biopsies were retrospective and included few and
selected patients. We described the natural history of liver fibrosis progression and relevant risk factors in a cross-
sectional study of single liver biopsy in a large number of patients for whom a reliable estimate of fibrosis had
been performed. The estimate was assessed primarily in patients for whom the duration of infection was known,
but its validity had been checked by indirect estimates using age at biopsy and in two smaller longitudinal studies
with repeated biopsies.
This study found a strong, almost linear, correlation of fibrosis stages with age at biopsy and duration of infection.
This correlation was not observed between activity grades (Fig. 3). Therefore, fibrosis stages are more
representative of disease progression in comparison with activity grades. Although hepatitis C is a viral disease, it
is mainly a fibrotic disease. Mortality and complications are related to cirrhosis. The clinical hallmarks of major
necrosis and inflammation (i.e., severe acute hepatitis and fulminant hepatitis) are very rare compared with
hepatitis B. Even in immunologically compromised patients, there are very few acute flare ups in patients with
chronic hepatitis C.
Dynamic View of Fibrosis Progression
Because of the informative value of fibrosis stage, it is of interest for clinicians to assess the speed of the fibrosis
progression. We observed that fibrosis progression rate was not normally distributed (median, 0.133 METAVIR
grade per year, lower than the mean 0.252) but rather, asymmetric. The distribution suggested the presence of at
least three populations: one population of "rapid fibrosers," a population of "intermediate fibrosers," and one
population of "slow fibrosers." Therefore, the computation of a mean (or median) fibrosis progression rate per year
and of a mean expected time to cirrhosis does not signify that the progression to cirrhosis is universal and
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inevitable. Using the median fibrosis progression rate, the median expected time to cirrhosis in untreated patients
was 30 years; 33% of patients had an expected median time to cirrhosis of less than 20 years and 31% will
progress to cirrhosis in more than 50 years, if ever (Fig. 4).
Different Estimates of Fibrosis Progression
Limitations of any estimate of fibrosis include the difficulty in obtaining paired liver biopsies, the necessity for large
numbers of patients to achieve statistical power, and the sample variability in fibrosis distribution. Even in
published randomized trials, fewer than 50% of included patients undergo a second liver biopsy after the end of
the treatment. Because the time elapsed between biopsies is relatively short (usually between 12 and 24
months), the number of events (transition from one stage to another) is rare. Therefore, the comparisons between
fibrosis progression rates requires a large sample size to observe significant differences. The slope of progression
is difficult to assess because there is no large database with several biopsies. Therefore, the real slope is
currently unknown, and even if there is a linear relationship between stages and age at biopsy or duration of
infection, other models are possible. Furthermore, liver biopsy has its own limitations in assessing liver fibrosis.
Although it is the gold standard to score fibrosis, its value is limited by sample variability. At least a 10-mm-length
biopsy is mandatory to assess fibrosis accurately.
The assessment of fibrosis progression over time can be achieved by different methods. The observed (direct)
fibrosis progression rate is defined as the ratio of the difference in fibrosis stages between two biopsies,
expressed in METAVIR units, and the interval between the two biopsies in years. For example, for a patient with
fibrosis stage 2 at the first biopsy and stage 3 at the second biopsy performed 2 years later, the fibrosis
progression rate was 0.500 fibrosis units per year. The advantage of this assessment is that the exact duration is
known. The limitations are that the interval between biopsies is rather short (mean, 20 months) compared with the
mean time for transition between fibrosis stages (7 years) and that there is a risk of sampling and interpretation
errors for both biopsies.
The estimated (indirect) fibrosis progression rate per year is defined as the ratio between the fibrosis stage in
METAVIR units and the estimated duration of infection in years. In this model it is assumed that the patient has
no liver fibrosis the day of infection (stage F0) and that the fibrosis progression rate is constant. For example, for a
patient with fibrosis stage 2 and an 8-year duration of infection, the fibrosis progression rate was 0.250 fibrosis
units per year. The advantages of this assessment are the longer duration (mean, 16 years) and the absence of
variability at infection if the assumption of F0 is correct. The limitations are that the duration of infection may be
unknown and, even when known, it remains an estimate (i.e., it is assumed that the first transfusion or the first
intravenous drug injection was the true date of infection). It is also possible that some patients already have a
degree of fibrosis (i.e., due to alcohol) on the day of infection.
Nonquantitative assessment of fibrosis progression can be obtained more simply by the percentage of patients
who worsen, improve or do not change their stage between two biopsies. The advantage of this assessment is
simplicity. The disadvantage is that it does not take into account the observation period and the lack of
discriminant power over short durations between biopsies. If these percentages (transition probability from stage
to stage) are used in Markov modelling, they have to be expressed by time units. This Markov transition modelling
has been used to reconstruct HCV epidemics in France (8). This modelling was possible only because age and
sex influences on fibrosis progression have been taken into account. The transition rates from normal liver at
infection to the different stages can also be estimated by time dependent modelling as actuarial curves.
Factors Associated withFibrosis Progression
Several factors clearly have been shown to be associated with fibrosis progression rate duration of infection, age,
male gender, consumption of alcohol, human immunodeficiency virus (HIV) co-infection, and low CD4 count. The
progression from infection to cirrhosis depends strongly on sex and age. Viral factors such as genotype, viral load
at the time of the biopsy, and quasispecies are not correlated with fibrosis.
Appropriateness of Liver Biopsy
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In chronic liver disease, several studies have evaluated the intra- and interobserver (pathologist) concordance, the
discordances among methods, and the sampling errors. For chronic viral liver disease, there were significant
concordances for standardized items, particularly for fibrosis staging.
Four randomized trials have compared different biopsy methods. For the diagnosis of cirrhosis, one trial observed
better sensitivity with laparoscopy versus percutaneous biopsy and another trial better sensitivity using the Tru-
Cut versus the Menghini needle. One trial reported larger sampling by ultrasound-guided anterior large-bore cutting
needle biopsy than with the intercostal Menghini technique, and less adverse events. One trial observed fewer
adverse events when ultrasound-guided biopsy was used (2 vs. 9%), whatever the needle used.
It is only very recent that the histologic standards defining a normal liver have been revisited. No scoring systems
have so far integrated a definition of normal liver in their own definitions.
Adverse Events and Mortality of Liver Biopsy
A summary of the published articles (with more than 200 patients) assessing severe adverse events and mortality
rates is given in Table 1. There was significant heterogeneity among the observed mortality rates, with a range
from 0 to 3.3/1,000. Risk factors identified were age and cirrhosis.
Indication of Liver Fibrosis Assessment in Hepatitis C Chronic Hepatitis C
Recent consensus conferences have stated that liver biopsy is mandatory in chronic hepatitis C with abnormal
alanine aminotransferase permitting grading and staging of the disease. It is stated that liver biopsy should be
performed before initiating treatment and that it is not known if and when repeat biopsy is necessary.
In chronic hepatitis C, liver biopsy is probably not mandatory in patients who need treatment whatever the results
of the biopsy, for example in patients who can contaminate other people or in patients who have extrahepatic
manifestations impairing the quality of life. Liver biopsy assesses the rate of disease progression when the date of
contamination is known (fibrosis progression rate) and improves the prediction of treatment response.
Diagnosis of Cirrhosis
Biopsy can also be viewed as necessary for the diagnosis of cirrhosis, which implies a different follow-up than in
noncirrhotic patients. In a patient with cirrhosis, for example, it is necessary to screen for varices and for
hepatocellular carcinoma.
When the cirrhosis is obvious, biopsy is not appropriate. There are few studies in the literature estimating the
predictive values for cirrhosis of clinical, biologic,41-42 or morphologic signs.49-53 The following signs potentially
have a high positive predictive value: firm liver, ascites, splenomegalia, spider angioma, prothrombin time lower
than 60%, high serum hyaluronate, and platelet count < 100,000. With ultrasound, liver surface nodularity and
reduction of portal flow velocity have the better predictive values. A reduction in the indications for biopsy could be
achieved by increasing the positive predictive value and the negative predictive value of surrogate cirrhosis
markers. A summary of the present informational value of cirrhosis markers in chronic hepatitis C is given in
Figure 5.
Acute Hepatitis C
In acute hepatitis C, because of the effectiveness of treatment and the high (80%) spontaneous evolution to a
chronic disease, a recommendation for treatment seems mandatory whatever the results of liver biopsy. Therefore,
liver biopsy is not recommended when the diagnosis of acute hepatitis C is certain.
Patients with Normal Transaminases
Another important issue is the ability to diagnose minimal disease without biopsy. Among HCV polymerase chain
reaction-positive patients with sustained normal transaminases despite a low median fibrosis progression rate,
only 20% have a normal liver (no activity and no fibrosis). Thirteen percent of such patients have extensive fibrosis
(METAVIR stage 2, 3 or 4), and for them treatment is mandatory. No surrogate markers currently permit us to
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identify these patients with minimal disease, and therefore we continue to biopsy such patients.
Patients with Several Causes of Liver Disease
One common issue is the influence of other risk factors on the fibrosis progression rate. It has been clearly
demonstrated that a daily alcohol consumption of 50 g/day or above is highly associated with enhanced fibrosis
progression rate. Similarly, the suspicion of associated hemochromatosis, autoimmune disease, nonalcoholic
steatohepatitis, or co-infection with hepatitis B should lead to liver biopsy. Liver biopsy helps clinicians to
estimate the specific impact of each factor.
Patients Co-infected with HIV Virus
Several studies have demonstrated that patients coinfected with HCV and HIV have a faster fibrosis progression
rate than controls even after taking into account age, sex, and alcohol consumption. The prevalence of cirrhosis is
three-fold higher in HIV-HCV co-infected patients than in HIV negative HCV-infected patients, and one third of co-
infected patients are at risk of dying of liver disease.
The progression of fibrosis is more rapid in coinfected patients compared with matched controls infected by HCV
alone. In co-infected patients, a low CD4 count (#200 cells/mL), alcohol consumption (>50 g/day), and age at
HCV infection are associated with a higher liver fibrosis progression rate.
Anti-HIV treatments are often associated with increased transaminases (stavudine, didanosine, abacavir,
nevirapine, protease inhibitor). When the increase is appreciable, another liver biopsy must be considered and
compared with biopsy before treatment. The following factors can be involved: alcohol consumption, illicit
intravenous drug injection, substitution drug toxicity, anti-HIV drug toxicity, co-infection with hepatitis B or delta
virus, opportunistic liver infection, immune restoration, and sclerosing cholangitis. The impact of immune
reconstitution on liver fibrosis progression is unknown.
Assessment of Liver Fibrosis Stage during or after Treatment
Together with the concept of assessing fibrosis progression rate during the natural history of chronic hepatitis C,
the concept of suppressive therapy has emerged as a new standard for the impact of treatments. It is possible
now to assess the impact of treatment on the fibrosis progression rate. Several studies have demonstrated that a
sustained viral response, obtained by interferon alone or by the combination of ribavirin and interferon, was
associated with a reduction in fibrosis progression and with stage regression. For nonresponders (60% of
patients) there is also now accumulating evidence that interferon treatment alone or in combination with ribavirin
has a suppressive effect on fibrosis progression. Serum markers of fibrosis or fibrogenesis have been evaluated in
small studies without identifying practical predictive values.
Conclusion
Liver biopsy is certainly appropriate for fibrosis staging of chronic hepatitis C. However, the appropriate role of liver
biopsy in a practical diagnostic/staging algorithm should be further evaluated. Excess requirements for liver
biopsy, because of its cost and risk, could actually become a barrier to treatment. By contrast, underuse of liver
biopsy could also lead to inappropriateness of hepatitis treatments. There is a major need for noninvasive markers
of liver fibrosis. None are useful today for the diagnosis of early stages.
Abbreviations
HCV: hepatitis C virus
HIV: human immunodeficiency virus
MMPs: matrix metalloproteinases
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