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Re: [GIWorld-Hepatitis] Article on Fibrosis and HCV-Marty

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  • Dee Dee Taylor
    Great Article......Thanks Marty......Dee ... _________________________________________________________________________ Get Your Private, Free E-mail from MSN
    Message 1 of 1 , Aug 31, 2000
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      Great Article......Thanks Marty......Dee

      >From: 2byteme@...
      >Reply-To: GIWorld-Hepatitis@egroups.com
      >To: GIWorld-Hepatitis@egroups.com
      >Subject: [GIWorld-Hepatitis] Article on Fibrosis and HCV-Marty
      >Date: Sat, 26 Aug 2000 19:57:30 -0400
      >Fibrosis in Patients with Hepatitis C:
      >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., and Pierre Opolon, M.D.
      >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.]
      >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
      >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 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.
      > Figures 1. (click image to zoom) The METAVIR
      > Fibrosis staging system. F0 is normal liver (no
      > fibrosis). F1 = portal fibrosis. F2 = few septa. F3
      > = many septa. F4 = cirrhosis.
      >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.
      > Figures 2. (click image to zoom) The model of
      > fibrosis progression from infection to
      > complications.
      >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.
      > Figure 3. (click image to zoom) Relationship
      > between age at biopsy and stage of fibrosis (panel
      > a), and grade of activity (panel b), and between
      > estimated duration of infection and stage of
      > fibrosis (panel c) and grade of activity (panel d).
      >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 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.
      > Figure 4. (click image to zoom) Progression of
      > liver fibrosis in patients with chronic hepatitis C.
      >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
      >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
      >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
      >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.
      > Figure 5. (click image to zoom) Ranges of
      > sensitivity and specificity of cirrhosis markers in
      > patients with chronic hepatitis C.
      >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 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
      >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.
      >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.

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