Gebo KA, Bass EB.
Johns Hopkins University School of Medicine, Baltimore, Maryland
In June of 2002, the National Institutes of Health (NIH) convened a consensus
development conference on the management of hepatitis C (1). This conference
differed from a previous conference (2) on management of hepatitis C by including
presentations from a detailed systematic review of evidence on key questions
(3-6) and presentations by leading experts in the field.
The Consensus Statement makes many important recommendations regarding the management
of chronic hepatitis C, but we would like to highlight the evidence on two aspects
of management that may not receive as much attention as the issue of treatment
choice. These aspects are 1. liver biopsy--should all patients with chronic
hepatitis C be referred for biopsy? and 2. hepatocellular carcinoma (HCC)--should
patients with chronic hepatitis C be screened for this disease?
Because these are questions that arise when patients are initially diagnosed
with hepatitis C, primary care physicians should be familiar with the Consensus
Statement and its supporting evidence.
Liver Biopsy
In patients with hepatitis C, liver biopsy provides information about fibrosis
and histology that clinicians may use to determine prognosis and treatment.
Liver biopsy also helps identify the presence of liver disease related to other
causes. Experts at the Consensus Development Conference advocated for the use
of liver biopsy primarily because biopsies may help in treatment decisions and
allow for monitoring of disease progression, and have a low risk of serious
complications (3%)(7). In particular, patients have a low risk of progression
to cirrhosis if they have persistently normal or slightly elevated alanine transaminase
levels with minimal or no fibrosis on biopsy. Such patients may think that the
potential adverse effects of antiviral treatment may outweigh the potential
benefit of treatment, at least until more fibrosis develops. The patients' views
may vary, depending on the hepatitis C virus (HCV) genotype, because the efficacy
of antiviral treatment is much better in patients with HCV genotype 2 or 3 than
in those with genotype 1.
To assess the utility of liver biopsy in predicting treatment response, we evaluated
randomized trials of treatment for chronic hepatitis C infection where treatment
assignment was not dependent on liver biopsy results and patients were followed
for at least 24 weeks after treatment ended (5). We found 12 studies that reported
at least some information on the relation of pretreatment histology to virologic
or histologic outcomes of treatment. In addition, six studies reported enough
data to enable an estimate of whether the difference in virologic response between
treatment regimens depends on pretreatment histology.
These studies were relatively consistent in finding that the presence of advanced
fibrosis or cirrhosis may predict a modest decrease in the likelihood of a virologic
response to any of the interferon-based treatment regimens evaluated in the
trials. The Consensus Development Conference Panel weighed this evidence along
with the testimony of clinical experts and concluded that "liver biopsy
is a useful part of the informed consent process regarding treatment" (1).
The Panel emphasized that a biopsy allows patients to make a more informed choice
about the initiation or postponement of treatment, although "the appropriate
interval for subsequent evaluations is yet to be determined" (1). Because
liver biopsy can cause morbidity and is expensive, some have questioned the
utility of liver biopsy and have recommended alternatives to assess the extent
of liver fibrosis (8,9). Therefore, we sought to identify biochemical or other
serologic tests that accurately predict the degree of fibrosis seen on liver
biopsy. We found that serum transaminase levels correlate only modestly with
the degree of fibrosis (5). Although some evidence suggested that the ratio
of aspartate transaminase to alanine transaminase was a relatively specific
indicator of significant fibrosis, that ratio had poor sensitivity for detecting
fibrosis.
New tests of extracellular matrix proteins, especially when combined into panels
of tests, were better than transaminase levels at predicting the presence or
absence of significant fibrosis. However, no serologic test, alone or in combination,
was able to consistently identify patients with intermediate stages of fibrosis
5). Accordingly, the Panel indicated that noninvasive tests could not replace
the information provided by a liver biopsy.
Hepatocellular Carcinoma Screening
The incidence of HCC in patients with hepatitis C ranges between zero and 1.6
percent per year.10 The risk of HCC is higher in patients with hepatitis C who
have cirrhosis--estimates range from 1 to 6 percent per year (11-15). Mortality
from HCC is substantial, with survival rates as low as 1 percent at two years
in untreated patients (16,17). Nevertheless, screening for HCC in patients with
hepatitis C infection has been a matter of controversy, because no randomized
controlled trials have demonstrated the efficacy of screening in this population.
Despite the lack of trial evidence, many physicians screen patients for HCC
with serum alpha-fetoprotein (AFP) levels or hepatic ultrasound examinations,
believing that screening will improve survival. Although we were unable to identify
any study demonstrating a screening or surveillance protocol that improved long-term
survival, one study18 suggested that HCC was detected earlier and was resectable
more often in patients who had twice-yearly screening with serum AFP determinations
and hepatic ultrasonography than in those who had usual care, but no survival
analysis was performed.
In addition, we evaluated studies that looked at performance characteristics
of different screening tests, including serum AFP and ultrasonography. The studies
demonstrated that the sensitivity and specificity of a serum AFP level in identifying
HCC depends on the thresholds used.4 For example, a threshold range from 10
to 19 ng per mL (10 to 19 mg per L) had a sensitivity of 75 to 80 percent and
a specificity of 65 to 80 percent, while a threshold value of 400 ng per mL
(400 mg per L) had a sensitivity of 4 to 48 percent, with a specificity of about
100 percent. Ultrasound studies reported variable sensitivities, between 11
and 100 percent, with a high degree of specificity (4).
Therefore, the Panel concluded that the value of screening for HCC is uncertain
because no data demonstrate the clinical impact of this screening on the management
of HCC or associated mortality.1 The Panel also concluded that hepatic ultrasonography
is more sensitive than serum AFP testing but is more expensive and can lead
to invasive and unnecessary follow-up tests. The Panel recommended that routine
screening for HCC not be performed in patients with hepatitis C in the absence
of cirrhosis because HCC is so rare in this group.
Because there were significant limitations of the evidence for both the liver
biopsy and the HCC screening issues, the Panel used both clinical expert opinion
and published evidence to arrive at these conclusions. Perhaps the most important
recommendations are that further studies should be done, particularly to "more
clearly establish the role of liver biopsy in the therapeutic management of
patients with hepatitis C" and "to assess screening tests in patients
at greatest risk of HCC" (1).
This editorial refers to research conducted by the Johns Hopkins Evidence-based
Practice Center under contract to the Agency for Healthcare Research and Quality
(Contract No. 290-97-0006), Rockville, Md. The authors of this article are responsible
for its contents, including any clinical or treatment recommendations. No statement
in this article should be construed as an official position of the Agency for
Healthcare Research and Quality or of the U.S. Department of Health and Human
Services.
________________________________________
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