Print this pageEmmet
B. Keeffe, M.D.
Stanford University Medical Center
Stanford, California
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The
traditional gold standard to establish the diagnosis and stage chronic liver
disease is liver biopsy. Historically, liver biopsy was the only diagnostic test
available for the evaluation of liver disorders and was recommended in virtually
all cases. However, chronic liver disease can now be accurately diagnosed, in
the majority of cases, by the use of contemporary blood tests for acute and
chronic hepatitis, autoimmune liver diseases, and hereditary liver diseases, or
a careful history of medication use for drug-induced liver disease, alcohol
abuse for alcoholic liver disease, and presence of risk factors (obesity,
diabetes mellitus, hyperlipidemia) for nonalcoholic fatty liver disease. In some
cases of liver disorders, such as hepatic granulomas and liver abnormalities
occurring after liver transplantation, liver biopsy is required for precise
diagnosis.
Expert
consensus groups from the United States and Europe have recommended the routine
performance of liver biopsy prior to initiation of antiviral therapy for chronic
hepatitis C (1,2). These recommendations were developed during the era of
interferon monotherapy, when the sustained virological response rate (SVR) for
patients with genotype 1 was less than 10% and for genotypes 2 and 3 was 15% to
30%. The rationale for a pretreatment liver biopsy at the time of these
consensus conferences was to distinguish patients who might potentially benefit
from interferon monotherapy, i.e., patients with significant fibrosis (stage 2
– portal fibrosis, stage 3 – bridging fibrosis, and stage 4 – cirrhosis)
from those less likely to benefit from therapy (stage 0 – no fibrosis or stage
1 – portal fibrosis). These recommendations led to the routine performance of
liver biopsy in nearly all patients who were newly diagnosed with chronic
hepatitis C and potential candidates for antiviral therapy.
Recent
studies have both supported and questioned the role of liver biopsy in patients
with known clinical diagnoses, such as chronic hepatitis C virus (HCV) infection
based on positive serological and virological blood tests. In an Italian study,
Andriulli et al (3) studied 535 patients with chronic viral hepatitis who had
undergone liver biopsy. Additional diagnoses were uncovered in only 4% of cases.
Knowledge of the grade and stage of chronic hepatitis were considered of value
by the treating physician in approximately 60% of cases, but antiviral treatment
was not changed in 81% of cases. These investigators concluded that liver biopsy
is less helpful than conventionally understood, because it generally neither
increases the accuracy of clinical diagnosis nor affects the choice of therapy.
On the other hand, Saadeh at al (4) agreed that liver biopsy did not yield new
diagnoses in patients with chronic hepatitis C, but concluded that biopsy
provided useful information regarding staging, prognosis, and decisions
regarding treatment.
Some
of the traditional arguments in favor of routine liver biopsy in patients with
chronic HCV infection can be questioned (5). Firstly, biopsy is proposed to be
important to reveal an unsuspected secondary liver diagnosis, but the studies
noted above did not support this argument. Secondly, liver biopsy is recommended
to diagnose unsuspected cirrhosis, which may change the prognosis and
considerations regarding therapy or follow-up (e.g., screening for
hepatocellular carcinoma with regular alpha-fetoprotein and ultrasound).
However, the finding of cirrhosis did not influence the decision for treatment
in the study of Andruilli et al (3), as all patients were treated with antiviral
therapy. In addition, noninvasive testing with imaging studies showing an
irregular surface of the liver and/or an enlarged spleen and blood tests showing
a low platelet count can often identify patients with advanced stages of
fibrosis, i.e., bridging stage 3 fibrosis or cirrhosis. Thirdly, and most
convincing, is the performance of liver biopsy to established the grade and
stage of chronic hepatitis C. However, cost-effective analyzes and patient
preferences, with the recent improvements in the SVR after antiviral therapy for
chronic hepatitis C, may be more dominant influences in decisions regarding
antiviral therapy than findings on biopsy.
Patients
with chronic hepatitis C are often anxious regarding undergoing a liver biopsy,
and many would prefer to avoid a biopsy. Patients frequently have anticipatory
anxiety, which would be expected of a procedure that is associated with pain in
30%, severe complications in 3 per 1000, and death in 3 per 10,000 of patients
(6). Some patients prefer to defer rather than undergo current therapy if they
have no or minimal fibrosis because of side effects, but are agreeable to
therapy if they have advanced fibrosis – in this case a liver biopsy is
necessary. As the outcomes of therapy have improved with the advent of
combination treatment with interferon and ribavirin in 1998 and now
peginterferon and ribavirin in 2001 (SVR of ~45%
for genotype 1 and ~80%
for genotypes 2 and 3) (7,8), more patients prefer empiric therapy in an attempt
to achieve a SVR irrespective of whatever liver biopsy might show. Finally, some
patients not only opt for therapy but also want to know their degree of hepatic
fibrosis as a general indicator of prognosis. Thus, clinicians may not need to
routinely perform routine liver biopsies in all patients with chronic hepatitis
C and might consider using biopsy selectively, rather than routinely, to assist
in decisions regarding therapy taking into account patient preferences after
full education regarding the options (5).
There
are a number of pretreatment factors that predict the success of antiviral
therapy, of which genotypes 2 or 3, low viral load (< 2 million IU/mL), and
early stages of fibrosis (stages 0 to 2) on liver biopsy are the most important.
These factors can be used to predict a relatively better or worse than average
chance of achieving a SVR. There are also evolving studies showing that early
virological responses at different time points after beginning therapy, e.g., 12
weeks, are additional factors that may predict the likelihood of a SVR. In the
study of Fried et al (8), a 2 log10 drop or negative HCV RNA occurred
at 12 weeks in 86% of patients treated with peginterferon alfa-2a and ribavirin,
and 65% of these patients had a SVR. Thus, patients who have favorable
pretreatment predictors noted above, especially genotypes 2 or 3 with an
approximate 80% chance of a SVR, and are motivated to eradicate HCV might
reasonably forgo a liver biopsy. Those who have unfavorable pretreatment
predictors of success of therapy, such as genotype 1 and a high viral load,
might be the best candidates for liver biopsy to influence the decision of
whether or not to initiate therapy. Once therapy is initiated in patients not
having a pretreatment liver biopsy, it is also possible to obtain a later liver
biopsy during therapy, e.g., in patients not meeting early predictors of a SVR
after 12 weeks of therapy. Patients found to have advanced fibrosis may warrant
continuation of therapy even though the chance of success is relatively low. A
biopsy might also be used after therapy is initiated if there is poor tolerance
to treatment with either systemic and psychiatric side effects or bone marrow
depression. The presence of advanced fibrosis might influence the decision to
continue therapy and use adjunctive therapies such as antidepressant drugs for
serious psychiatric side effects or G-CSF for leukopenia or epoetin for anemia.
In
conclusion, all patients with chronic hepatitis C who are candidates for
antiviral therapy may not need to undergo a procedure for which there is much
apprehension, a finite complication rate, and personal and societal costs. Some
clinicians are moving to selective rather than routine use of liver biopsy in
patients with chronic HCV infection, reserving biopsy for circumstances in which
biopsy would influence the decision regarding either initiation or continuation
of therapy. It is of paramount importance that liver biopsy should not be a
barrier to therapy; patients not desiring a biopsy should not be denied therapy.
It is also important to make a distinction between physicians in private
practice seeking a practical approach to the management of chronic hepatitis C
versus investigators at tertiary centers, who are enrolling patients in
pharmaceutically funded clinical trials or prospectively collecting liver biopsy
data for their own research. Physician investigators are the usual educators
across the country and generally have a bias in favor of routine liver biopsy
based on the importance of liver biopsy in research studies. Better noninvasive
markers, either newer blood tests that are markers of hepatic fibrosis or
various formulae based on miscellaneous clinical and laboratory tests, to
predict the stage of fibrosis without liver biopsy are needed. In addition,
pretreatment and early treatment predictors with a high positive predictive
value of a SVR also require further refinement to allow selection of patients
with a high likelihood of success with antiviral therapy irrespective of liver
biopsy findings.
References
1.
National Institute of Health Consensus Development Conference Panel
statement: management of hepatitis C. Hepatology 1997;26(suppl 1):2S-10S.
2.
European Association for the Study of the Liver. Consensus statement.
EASL international consensus conference on hepatitis C. J Hepatol
1999;30:956-61.
3.
Andriulli A, Festa V, Leandro G, Rizzetto M, and AIGO Members. Usefulness
of a liver biopsy in the evaluation of patients with elevated ALT values and
serological markers of hepatitis viral infection. An AIGO study. Dig Dis Sci
2001;46:1409-15.
4.
Saadeh S, Cammell G, Carey WD, et al. The role of liver biopsy in chronic
hepatitis C. Hepatology 2001;33:196-200.
5.
Garcia G, Keeffe EB. Liver biopsy in chronic hepatitis C: routine or
selective (Editorial). Am J Gastroenterol 2001;96:3053-5.
6.
Piccinino F, Sagnelli E, Pasquale G, et al. Complications following
percutaneous liver biopsy: a multicenter retrospective study on 68,276 biopsies.
J Hepatol1986;2:165–73.
7.
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus
ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment
of chronic hepatitis C: a randomised trial. Gut 2001;358:958-65.
8.
Fried MW, Shiffman ML, Reddy RK, et al. Pegylated (40 kDA) interferon
alfa-2a (Pegasys®) in combination with ribavirin: efficacy and safety results
from a phase III, randomized, actively-controlled, multicenter study (Abstract).
Gastroenterology 2001;120:A55.