INFO: Role of Liver Biopsy in Chronic Hepatitis C

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Role

of Liver Biopsy in Chronic Hepatitis C

Emmet

B. Keeffe, M.D.

Stanford University Medical Center

Stanford, California

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

National Institute of Health Consensus Development

Conference Panel statement: management of hepatitis C. Hepatology 1997;26(suppl

1):2S-10S.

European Association for the

Study of the Liver. Consensus statement. EASL international consensus

conference on hepatitis C. J Hepatol 1999;30:956-61.

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.

Saadeh S, Cammell G, Carey

WD, et al. The role of liver biopsy in chronic hepatitis C. Hepatology

2001;33:196-200.

G, Keeffe EB. Liver

biopsy in chronic hepatitis C: routine or selective (Editorial). Am J Gastroenterol

2001;96:3053-5.

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.

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.

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.

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