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Role of Liver Biopsy
Liver biopsy plays a central role in the evaluation of chronic liver diseases, including HCV infection. In 1997, a National Institutes of Health (NIH) Consensus Development Conference Panel endorsed liver biopsy prior to the initiation of treatment of HCV infection.21 In 2002, another NIH consensus conference noted: "Liver biopsy provides a unique source of information on fibrosis and assessment of histology. Liver enzymes have shown little value in predicting fibrosis. Extracellular matrix tests can predict severe stages of fibrosis but cannot consistently classify intermediate stages of fibrosis. Moreover, only liver biopsy provides information on possible contribution of iron, steatosis, and concurrent alcoholic liver disease to the progression of chronic hepatitis toward cirrhosis. . . . Thus, the liver biopsy is a useful part of the informed consent process. . . . Since a favorable response to current antiviral therapy occurs in 80% of patients with genotype 2 or 3, it may not always be necessary to perform liver biopsy in these patients." 22
The histologic features of chronic HCV infection are well defined. Two components are considered: activity and fibrosis. Activity. Activity is gauged by the number of mononuclear inflammatory cells present in and around the portal areas, and by the number of dead or dying hepatocytes. Changes in activity do not imply progressive disease. Fibrosis.
The fibrotic response to HCV infection is variable. Fibrosis
implies possible progression to cirrhosis. In mild cases, fibrosis
is limited to the portal and periportal areas. More advanced changes
are defined by fibrosis that extends from one portal area to another.
The term for this is "bridging fibrosis". In some, this
reaction evolves into cirrhosis.
Fibrosis, more than inflammation, predicts the progression to irreversible liver disease in HCV infection. The METAVIR system is simple and easy to learn, and it has been extensively validated (Table 7).27
For all its advantages, liver biopsy has several important disadvantages. Among them are cost, the risk of complications, the need for additional health care resources, patient and physician aversion to the procedure, inadequate specimen size, and the lack of specific findings. Cost. Liver biopsy adds between U.S. $1,500 and U.S. $2,000 to the cost of an evaluation. Complications. Approximately 20% to 50% of patients will experience significant
pain following percutaneous liver biopsy. More severe complications—such
as pneumothorax, major bleeding, inadvertent biopsy of the kidney
or colon, and perforation of the gallbladder—have been reported
in a fraction of patients (0.57%). There have even been a few reports
of death.28 29 Patient aversion. Patients find liver biopsy anxiety provoking, even when the procedure goes well. Some specialists now advise premedication with anxiolytic agents to reduce apprehension—for example, midazolam, 1 to 2 mg IV, or lorazepam, 1 mg po, before the procedure. Some use meperidine, 12.5 to 25 mg IV, before biopsy to improve comfort. Additional narcotic analgesia may be necessary if post-biopsy pain is more than mild. Physician aversion. A recent survey of 112 gastroenterologists in the southeastern United States revealed that between one-quarter and one-third do not perform liver biopsies because they are concerned about complications and low reimbursement.30 These respondents said they refer patients to a radiologist for liver biopsy. More than three-quarters (77%) routinely biopsy all HCV-infected patients before treatment, and the others biopsy selected HCV-infected patients to assist in decision-making. Only 3.6% do not biopsy any patients before treatment. Post-treatment biopsies are performed much less frequently. Seven percent of the surveyed physicians routinely biopsy all patients after treatment. Ultrasonography is used as a guide to biopsy selection site by nearly one-half (47%), although it is used by only 5% when the biopsy is performed by the gastroenterologist. A recent observational
study of 166 HIV/HCV-coinfected injection-drug users in France found
that 45% underwent liver biopsy during a 5-year follow-up period;
factors predictive of liver biopsy were high social support, complete
abstinence from drugs, lack of immunosuppression, male gender, lack
of multiple incarcerations, recent onset of drug use, and increased
liver enzyme levels.31 A recent study
of "virtual biopsy specimens" confirmed that the amount
of liver tissue available for the pathologist to review is critical.34
A biopsy length of 15 mm was 65% accurate in scoring the degree
of fibrosis; a biopsy length of 25 mm was 75% accurate. Specimens
longer than 15 mm that contain six or more portal areas correlate
better with biochemical surrogate markers of fibrosis than do smaller
specimens.35
The utility of
liver biopsy in routine cases of HCV infection has been challenged
on the basis that clinical and laboratory parameters alone provide
sufficient information to make a decision for or against antiviral
therapy.39 Liver biopsy
is not necessary to establish the diagnosis of HCV infection. Serum-based
tests are precise and unequivocal, and a positive HCV RNA test confirms
infection. In the absence of other clinical or laboratory findings
suggesting the possibility of a second liver pathology, a liver biopsy
will not alter the diagnosis. A study at the Cleveland Clinic found
that no case of HCV infection diagnosed by serum-based tests was overturned
by liver biopsy findings.40
Moreover, in only 2% of cases was an additional liver diagnosis made.
Cirrhosis is found in approximately 29% of unselected cases of HCV infection that come to biopsy.40 Clinical and laboratory tests are relatively weak predictors of the extent of liver damage caused by HCV infection. The number of HCV-infected patients whose liver disease staging (either advanced fibrosis or, conversely, no fibrosis) can be confidently predicted by the AST:ALT ratio, the international normalized ratio (INR), and the platelet count is low. A published cirrhotic discriminant score (Bonacini) for the clinical diagnosis of cirrhosis correctly established or excluded a diagnosis of cirrhosis in only 23% of cases.40 In the remainder, liver biopsy was critical for proper staging. These findings have recently been confirmed by other groups.39 41 Others have also found that predicting severe cirrhosis or fibrosis on the basis of laboratory tests (eg, AST:ALT ratio, platelet counts, and measurements of hyaluronic acid, fibronectin, pseudocholinesterase levels, etc) is not sufficiently sensitive.42 Recently, new attempts to stage hepatitis C according to serum-based indices have been offered. Investigators have suggested that biochemical markers of liver fibrosis in patients with HCV infection allow for satisfactory staging of disease in many, if not most, HCV-infected patients.43 The fibrotest has been used to assess the histologic effects of antiviral therapy.35 Table 8 lists those markers that have been combined in various ways to detect fibrosis.
Although the calculated fibrosis score rises with increasing degrees of histologic fibrosis, the overlap in serum-based scores in different histologic METAVIR grades limits the clinical utility of this approach (Figure 3). Others have proposed a simpler model,44 based on an AST:platelet ratio index calculated as follows: AST:platelet ratio index = [(AST/ULN)/platelet count] X 100 where the platelet
count is expressed as 109/L and ULN stands for upper
limit of normal. This index, if properly validated, may be clinically
useful.
The need for liver biopsy in HCV infection should be predicated on the type of information that is being sought for an individual patient. The presence or absence of cirrhosis is clinically relevant in many cases where therapy with antivirals is being considered. All other features being constant, the presence of bridging fibrosis or cirrhosis markedly reduces the expected response rate to antiviral therapy. Major shifts in expected outcomes are far from trivial and will often alter the clinical decision to treat.45 In addition to identifying a lesser chance of successful viral elimination, the goal of prevention of cirrhosis becomes moot if cirrhosis is present on pretreatment biopsy. Additional management changes often mandated by finding cirrhosis include entry into surveillance programs for hepatocellular carcinoma and for esophageal varices. Liver biopsy
remains an important tool in the baseline evaluation of the HCV-infected
patient. A specimen of sufficient length (15 mm) and width (1.4
mm) that contains at least six portal areas is desired. How frequently
sequential biopsies should be performed in the HCV-infected patient,
if at all, has not been established. There appears to be little
need for routine biopsies following a course of antiviral therapy.
Authorities differ in clinical practice with respect to follow-up
biopsies at various intervals to restage the liver in HCV infection.
We do not recommend routine follow-up biopsies.
Alcohol is well recognized as a cofactor in the progression of hepatitis C, and alcohol consumption during anti-HCV therapy reduces response to treatment. While abstinence from alcohol is strongly recommended during treatment of HCV infection,22 safe levels of alcohol use outside the context of therapy are less certain. Abundant data demonstrate a correlation between heavy alcohol use (>60 g/d in men and >40 g/d in women) and advanced grades of fibrosis in patients with hepatitis C,46 47 but the effect of mild or moderate alcohol use has been less clear. In a recent study assessing the effects of a range of alcohol intake levels on fibrosis in HCV-infected patients, Monto et al reported no association between light (0 to 20 g/d) or moderate (20.1 to 50 g/d) alcohol use and mean fibrotic score.48 Heavy alcohol use (>50 g/d) was associated with a significant increase in mean fibrotic score. Multivariate analysis showed that age, serum ALT level, and histologic inflammation were the only independent predictors of fibrotic score, leading the researchers to conclude that factors other than alcohol intake predominate in the development of hepatic fibrosis. This trial, the largest and best-designed study of the question to date, puts in doubt previous "certainty" that mild to moderate alcohol use contributes to progression of noncirrhotic HCV-related liver disease. While discouragement of alcohol use is prudent for all patients with chronic HCV infection, how dogmatic clinicians should be in discouraging mild to moderate alcohol consumption outside the context of therapy is open to debate.
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