Do All Patients With Chronic Hepatitis C Virus Require a Liver Biopsy?
Liver biopsy has long been utilized as a tool to both diagnose and or confirm the specific etiology of liver disease and to assess disease severity. The biopsy can be performed via percutaneous, transjugular, or laparoscopic techniques. The risk of complications associated with liver biopsy ranges from 0.5% to 2%. Bleeding complications occur most commonly in patients with thrombocytopenia or an elevation in INR and when a vascular mass is biopsied. In most large series, the risk of complications associated with diagnostic percutaneous liver biopsy in patients without laboratory evidence of cirrhosis was only 0.01% to 0.1%.1 This is similar if not slightly lower than the risk of hemorrhage reported in patients who have a large poly removed during colonoscopy. It is therefore interesting that many gastroenterologists shy away from performing a liver biopsy, citing the high rate of complications, yet will gladly remove a large poly with the utmost of confidence.
Several systems have been developed to stage and grade the biopsy specimen. Most pathologists use the method they were taught during their training and are most comfortable with. Table 3-1 summarizes the most popular biopsy scoring systems. The precise numerical score is really not important. What is critical is that you understand how much inflammation (biopsy grade) and fibrosis (the stage) is present in the liver so that you can relate this to the patient in a manner he or she can understand. We tend not to fixate on the score but rather tell a patient he has either no, mild, moderate, or severe fibrosis (scarring) or cirrhosis. Patients tend to understand this much better.
The grade of the biopsy is important because it is the degree or intensity of inflammation that causes fibrosis progression. Thus, patients with no fibrosis and very mild inflammation have a very low rate of progression to cirrhosis. The majority of patients with mild inflammation and no fibrosis have persistently normal serum aminotransferases. Less than 20% of such patients develop any degree of fibrosis progression after 20 years. Patients in this category who do progress were probably understaged because of sampling error on the initial biopsy. In contrast, patients with significant degrees of inflammation will develop fibrosis progression. In general, there is a stepwise relationship between the severity of inflammation and the degree of fibrosis.
Are There Alternatives to Liver Biopsy?
The perceived risk and discomfort associated with liver biopsy have led to the development of several noninvasive methods to assess liver fibrosis. These include serum fibrosis markers, indexes that are calculated from standard blood tests and new imaging techniques. All of these noninvasive tests were developed in patients with chronic HCV and their utility in patients with other liver disorders, particularly cholestatic and noninflammatory liver disorders, remains unproven.
The AST/platelet ratio index (APRI) can be calculated from standard blood tests without additional cost.2 AST is expressed as a function of the upper limit of normal (AST/upper normal value for AST × 100). As the degree of fibrosis increases, the AST increases with respect to the upper limit of normal and the platelet count declines. As patients develop advanced fibrosis and then cirrhosis, this ratio increases exponentially. Values greater than 1.5 are strongly indicative of advanced fibrosis or cirrhosis. In contrast, the test is unable to differentiate between patients with no or mild fibrosis. However, if the APRI index is increasing consistently over time, it is likely that fibrosis is progressing. The test was developed in patients with chronic HCV and it remains unclear whether this ratio correlates with fibrosis in other forms of chronic liver disease.
The Fibrotest was developed retrospectively by correlating the liver fibrosis score in patients with chronic HCV to a vast array of serum biochemical and hematologic markers.3 Five markers (alpha-2-macroglobulin, haptoglobin, gamma-glutamyl transpeptidase, total bilirubin, and apolipoprotein A1) were selected though multivariate analysis. It is interesting to note that all of these biochemical tests are affected by inflammation and that none are precursors of fibrosis. These markers correlate with fibrosis because inflammation increases with the severity of fibrosis in patients with chronic HCV. It is unclear how these markers would perform in cholestatic and noninflammatory liver disorders.
The FibroScan is a specialized ultrasound unit that utilizes transient elastography to assess liver fibrosis.4 Sound waves are sent into the liver and the speed at which these waves return to the transducer is related to the degree of liver stiffness, which increases with increasing fibrosis. The FibroScan device is not yet FDA approved. The accuracy of FibroScan appears to decline with obesity, either because the distance between the probe and the liver is increased by adipose tissue and this affects the elasticity measurements or because of the presence of coexistent NAFLD.
Each of these noninvasive tests of liver fibrosis can accurately differentiate patients with significant fibrosis (more than portal fibrosis) from patients with lesser degrees of fibrosis. However, neither of these tests can accurately differentiate patients with advanced bridging fibrosis and cirrhosis or differentiate patients with no fibrosis from patients with mild fibrosis. The ability to accurately identify patients with chronic HCV and no fibrosis and mild inflammation is important because these patients may never develop fibrosis progression and therefore may not require treatment.
How Does the Assessment of Liver Histology Help in Selecting Patients Who Require Treatment for Chronic HCV?
Many patients who find out that they have chronic HCV have risk factors that date back 10 to 30 years and, therefore, they have likely had chronic HCV for this long. If such a patient is found to have no fibrosis on liver biopsy, then HCV has obviously not caused any fibrosis to develop in 25 years. Such a patient is likely to have an excellent prognosis and is very unlikely to develop any fibrosis in the future.5 Treatment is not necessary in these patients and will not alter the long-term prognosis, which is already excellent without treatment. However, if a patient is found to have any degree of fibrosis, he or she is likely to develop more fibrosis in the future and be at risk to develop cirrhosis. Such patients should be treated before they develop more advanced fibrosis since this is one factor that reduces the effectiveness of peginterferon and ribavirin therapy in patients with chronic HCV.
Many patients with chronic HCV are overweight and have type 2 diabetes mellitus and/or other factors associated with the metabolic syndrome. Such patients may have coexistent nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH). Several studies have clearly demonstrated that patients with chronic HCV and NAFLD or NASH have more advanced fibrosis and have a reduced response to peginterferon and ribavirin compared to patients without coexistent NAFLD. This information cannot be obtained by noninvasive liver fibrosis tests.
Which Patients Should Undergo Liver Biopsy Prior to Initiating Treatment for Chronic HCV?
The potential uses for liver biopsy and the noninvasive fibrosis tests are listed in Table 3-2. It is not necessary to assess liver histology in all patients prior to initiating peginterferon and ribavirin treatment. Rather, liver histology should only be assessed when this information would aid in the management of the patient’s liver disease. For example, if a patient with chronic HCV wants to be treated and would accept the adverse events associated with peginterferon and ribavirin even if a liver biopsy demonstrated no fibrosis, there is obviously no reason to perform a liver biopsy. For that matter, there is also no reason to perform any test to assess liver histology in such a patient. Most patients with chronic HCV genotypes 2 and 3 fall into this category because the rate of sustained virologic response (SVR) is high and treatment is for a shorter duration in most of these patients. However, such patients should have an assessment of liver histology if they fail to achieve an SVR. This would be necessary to determine whether the patient requires retreatment or can be safely monitored until more effective therapy is available.
If a patient with chronic HCV is worried about the adverse events of peginterferon and ribavirin and unsure if he really wants to receive treatment, then performing a liver biopsy is essential. None of the noninvasive tests can substitute for liver biopsy at this time since these tests cannot conclusively differentiate patients with no fibrosis from those with mild fibrosis. This is important because patients with mild fibrosis develop fibrosis progression and patients with no fibrosis may not. However, if a noninvasive test suggests that significant fibrosis is present, this information may be sufficient and a liver biopsy may not be necessary to confirm the exact degree of fibrosis. This is especially true if the noninvasive test suggests advanced fibrosis or cirrhosis since all of the noninvasive tests have excellent accuracy in this group. In contrast, if the noninvasive test suggests that mild fibrosis is present, a liver biopsy should be performed to determine just how mild this is and if no fibrosis is present.
Noninvasive tests of liver fibrosis are probably best utilized in specific populations where either the risk or cost of performing a liver biopsy is prohibitive. The most obvious patient populations in this group include those with hemophilia and patients who are incarcerated. Another potential use for noninvasive markers is to monitor for evidence of fibrosis progression in a patient with mild disease who either deferred treatment or failed to achieve an SVR during a previous course of treatment. However, these tests must be utilized with caution for this indication since no prospective data are currently available to inform us just how much of a change in the value of a noninvasive marker is significant and how much of a change in the noninvasive test needs to occur before this would be seen on liver biopsy.
Although the information provided by liver biopsy is generally useful, it is not necessary to perform this test in every patient prior to initiating treatment with peginterferon and ribavirin. Noninvasive tests of liver fibrosis are currently available. These are very accurate in identifying patients with advanced fibrosis or cirrhosis but have poor accuracy in identifying patients with no fibrosis who could easily defer or avoid HCV treatment. Patients who want to be treated for HCV even if they have no fibrosis do not need a biopsy or, for that matter, any other test to assess liver fibrosis. Probably the best use of noninvasive fibrosis markers is in those patients where liver biopsy is associated with increased risk and cost—the patient with hemophilia and the patient who is incarcerated.
1. Janes CH, Lindor KD. Outcome of patients hospitalized for complications after outpatient liver biopsy. Ann Intern Med. 1993;118:96-98.
2. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518-526.
3. Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J. Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin. Hepatology. 2003;38:481-492.
4. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343-350.
5. Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology. 2003;124:97-104.