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Diagnosing Fibrosis in Hepatitis C: Is the Pendulum Swinging from Biopsy to
Blood Tests?
The following editorial by NH Afdhal of the Liver Center, Beth Israel Deaconess
Medical Center, Boston, MA appears in the current (May 2003) issue of
Hepatology.
- See also the Letter to the Editor of Hepatology on this subject.
"One of the major clinical problems facing the hepatology and gastroenterology
community is how best to evaluate and manage the increasing numbers of patients
identified with hepatitis C virus (HCV). In the last decade, advances in
serologic and virologic testing for HCV and improvements in therapy have led
more patients to be identified and to seek treatment.
However, little progress has been made in improving either our ability to
determine the degree of hepatic injury, particularly fibrosis, or to predict the
risk of disease progression for the individual patient. This information still
requires an old fashioned liver biopsy.
The clinician relies on the biopsy results for both prognostic and therapeutic
decision making, which can have a major impact on the patient's life. While we
certainly are daunted at the prospect of performing 3 million liver biopsies
with the associated cost, manpower issues, and risk for patient injury, we need
to have a reliable alternative that can just as effectively guide our decision
analysis.
"Multiple histologic scoring systems have been proposed for the grading of HCV
inflammation and the staging of HCV fibrosis, including the commonly used
METAVIR and Ishak scoring systems. The pathologist is able to use these systems
to grade the inflammatory component of HCV and stage the degree of fibrosis.
Repeat liver biopsies can determine the effect of therapy on improving liver
inflammation and fibrosis and the true rate of disease progression in
individuals who decline therapy. Perhaps the first question we should ask is,
how good is our gold standard of liver biopsy for staging HCV-induced liver
fibrosis? A single-pass liver biopsy is able to correctly diagnose the stage of
fibrosis or presence of cirrhosis in 80% of patients.
Factors that improve the diagnostic accuracy of liver biopsy include the
presence of a uniform disease throughout the liver such as HCV, multiple passes,
use of a Trucut 15-gauge needle rather than Menghini type needles, and an
unfragmented biopsy core of 2 cm or greater in length. Even with experienced
physicians performing the liver biopsy and expert pathologists interpreting the
biopsy, our gold standard has up to a 20% error rate in staging disease.
"In addition, the actual role of liver biopsy in HCV is controversial. The liver
biopsy is not necessary to make the diagnosis and rarely is it of value in
excluding secondary diagnoses such as coexistent, autoimmune, iron, nonalcoholic
steatohepatitis or alcohol-induced injury.
The major clinical utility of the index biopsy in HCV is to enable the clinician
to determine the need for therapy. Because of the complexity and side effects of
interferon-based therapies for HCV, the liver biopsy has taken an increasing
role in the clinician's decision whether to treat a patient.
Patients with significant liver fibrosis (METAVIR
inflammation are all considered as suitable for therapy, whereas patients with
milder disease are often not as aggressively offered treatment. However, as
therapy for HCV improves, the clinical need for a biopsy may be less apparent.
For example, genotype 2 and 3 patients have a greater than 70% sustained
virologic response with pegylated interferons and ribavirin, and in
uncomplicated cases a rationale can be made to treat all these patients without
liver biopsy and only to biopsy those who fail treatment.
As newer, better tolerated, and more efficacious therapies are developed, the
need for biopsying all HCV patients to grade and stage disease may become
redundant. Therefore, the development of noninvasive tests that can
differentiate between patients with mild disease (METAVIR F0 or F1) versus those
with more significant fibrosis (METAVIR F2-F4) could have a widespread clinical
utility in managing HCV patients in the future.
This concept of attempting to use noninvasive serum tests to classify patients
as having mild or significant liver fibrosis was addressed in a recent
publication by Forns et al. and in several letters in this issue of Hepatology.
Forns examined a selected cohort of patients with HCV and, by using multiple
logistic regression, identified age and 3 commonly performed serum tests that
could be used to predict patients with F0/F1 disease. They derived a formula
giving a numerical score in an initial population of 351 HCV patients, which was
based on the patient age combined with single estimations of glutamyl
transpeptidase (GGT), cholesterol level, and platelet count.
This score was then validated in a prospective group of 125 patients, in which
92 patients had mild fibrosis and 33 patients had significant fibrosis. A score
of less than 4.2 was seen in 47 patients of whom 45 (96%) had stage F0/F1 giving
an overall accuracy of 96% in identifying patients with mild fibrosis. A score
of greater than 6.9 was taken as the high cutoff point for significant fibrosis.
Only 10 of 33 patients with stage F2 to F4 were identified by this scoring
system, and 15 patients with F0 to F1 were incorrectly classified as having
advanced disease. The authors concluded that this relatively simple, inexpensive
fibrosis scoring system could prevent the need for a liver biopsy in one third
of patients with mild disease.
Certainly, on preliminary analysis this looks promising but there are several
important considerations. First, the patient population was highly selected to
exclude patients over 65 years of age, those with regular alcohol consumption,
obese patients, and patients coinfected with HBV or human immunodeficiency
virus.
More importantly, only 51% of the patients studied could actually be classified,
and the scoring system was indeterminate for the remainder of the patients who
scored between 4.2 and 6.9. Therefore, the widespread applicability of such a
fibrosis scoring system might be limited.
Interestingly, two separate groups have validated the findings of Forns et al.
in separate cohorts of HCV patients. Patel et al. in their letter in this
edition of HEPATOLOGY applied the Forns scoring system to 110 HCV patients.
A score of less than 4.2 had a negative predictive value of 89%, but 59% of
patients were again in the indeterminate group and could not be classified.
Thabut et al. in their letter compare the Forns score to the previously
published FIBROTEST.
The FIBROTEST utilizes 5 less commonly used biomarkers for fibrosis including
apolipoprotein A1, haptoglobin, alfa 2 macroglobulin, GGT, and total bilirubin.
In their retrospective analysis, the FIBROTEST appeared slightly better at
diagnosing significant fibrosis and showed a more linear correlation with degree
of fibrosis than the Forns scale.
Both FIBROTEST and the Forns scale were excellent at excluding fibrosis, but the
FIBROTEST had a greater positive predictive value (90%) for diagnosing advanced
fibrosis. However, it is critical to point out that neither of these tests can
truly distinguish between the different histologic stages of fibrosis. In
addition, the FIBROTEST has similar issues with a large percentage of patients
falling into an indeterminate group.
The inability to classify large numbers of patients is not surprising because
neither of these systems really measures fibrosis but they both rather reflect
alterations in hepatic function associated with progressive disease. More
recently, combining markers of extracellular matrix (ECM) such as tissue
inhibitor of metalloproteinase and hyaluronic acid with alfa 2 macroglobulin, a
marker of hepatic function, has been evaluated by Patel et al. This combination
of fibrosis markers has a similar ability to differentiate F0/F1 from F2 to F4
and reduces the number of patients (20%-30% depending on fibrosis prevalence)
falling into the indeterminate range.
First, all of these investigators should be congratulated for pursuing
clinically relevant noninvasive methods to measure liver fibrosis. There is
little doubt that we need such surrogate fibrosis markers or scoring systems for
HCV, particularly as we start to develop a new generation of antifibrotic
therapies.
Several large studies are already in progress to evaluate both alfa and gamma
interferons as antifibrotic agents in HCV and all are relying on serial liver
biopsies as the primary outcome determinant. However, biopsies remain a static
determinant of the mass of fibrosis at a given time, and an antifibrotic agent
could be highly effective in ECM remodeling but show little change on biopsy.
This is where the utility of true fibrosis markers is critical. An ideal
noninvasive surrogate marker of liver fibrosis should be liver specific; not
influenced by alterations in liver, renal, or reticuloendothelial cell function;
reproducible; and easy to perform.
These markers should also reflect the stage of fibrosis for diagnostic purposes
and the dynamic balance of matrix deposition and removal. Finally, they should
be specific for liver fibrosis from any cause and be independent of any
associated hepatic inflammation.
Advances in our understanding of the hepatic ECM has led to many potential
markers being identified, but none have sufficient merit for clinical use as
solitary markers. A large multicenter European study combining multiple markers
that measure ECM production and breakdown has shown promise in the diagnostic
staging of liver disease, and further longitudinal studies from this cohort are
awaited.
So, are surrogate markers of liver fibrosis ready for clinical primetime? We
could argue from the study by Forns et al. and the FIBROTEST that we can, to
some extent, categorize almost a third of patients into those with mild disease
and use this information for decision analysis without a liver biopsy.
Unfortunately, there is somewhat of a rush to commercialize these so-called
tests of liver fibrosis without rigorous scientific validation. I would propose
that the clinical acceptance of fibrosis markers will depend on their fulfilling
the ideal characteristics listed above.
We need to focus basic and clinical research efforts on identifying better
fibrosis markers and exploring how to incorporate them into clinical practice.
The study of Forns et al. and others are a good beginning in our quest for
surrogate markers, but for the moment, the pendulum still favors biopsy over
blood."
05/02/03
Reference
NH Afdhal. Diagnosing fibrosis in hepatitis C: Is the pendulum swinging from
biopsy to blood tests? Hepatology 37 (5): 972-974. May 2003.
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