EDITORIAL
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LIVER
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Staging Liver Fibrosis in Hepatitis C: A Challenge for This Decade Michelle Lai, MD, MPH1 and Nezam H. Afdhal, MD1
Abstract: The limitations of and the invasive nature of liver biopsy has spurred extensive interest in the development of non-invasive tests to measure liver fibrosis in patients with chronic hepatitis C. Clinically applicable non-invasive tests, including radiological studies, elastography, and serum markers, all of which perform extremely well in excluding significant disease and diagnosing cirrhosis. FibroScan and acoustic radiation force impulse elastography are two elastography-based tests that show promise. In this new era of increased cure rates with newly Food and Drug Administration-approved drugs and the availability of multiple non-invasive tests of liver fibrosis, we anticipate a decreasing need for liver biopsies in the management of chronic hepatitis C. Am J Gastroenterol 2011; 106:2121–2122; doi:10.1038/ajg.2011.343
Rizzo et al. (1) address a very important clinical topic: staging of liver fibrosis in chronic viral hepatitis C (HCV) infection. Staging of liver fibrosis has important implications for disease prognosis and treatment decisions, although the importance of precise staging is diminishing as therapy for HCV is improving. The finding of advanced fibrosis would weigh in favor of starting treatment sooner rather than later. Diagnosing or excluding cirrhosis has major implications for patient outcomes and mandates radiological screening every 6 months for hepatocellular carcinoma and endoscopy to rule out portal hypertension (2). Traditionally, fibrosis staging has been done with liver biopsy. While liver biopsy is most accurate at the level of no fibrosis (stage 0) or cirrhosis, intermediate stages are prone to problems of sampling error, inadequate biopsy size, and inter-observer variability (3–6). The liver biopsy is 80% accurate, with a risk of both understaging and overstaging and cirrhosis can be missed in ~20% of patients (3–6). Liver fibrosis scoring systems based on liver biopsy were
initially designed for use in clinical trials for viral hepatitis. Besides metavir stage IV (cirrhosis), the clinical significance of lesser stages has not been validated in prospective outcome cohorts. The real clinical relevance between stage 1 and stage 2 fibrosis is not known with respect to either prognosis or risk of disease progression over the short to intermediate term of 5–10 years. A single biopsy does not account for the many factors associated with highly individually variable fibrosis progression and hence should not be used as the only method to predict the patient’s risk of disease progression. Due to limitations of and the invasive nature of liver biopsy, there has been extensive interest in developing non-invasive tests to measure liver fibrosis. There are alternatives to biopsy that can be used in clinical practice, with benefits in terms of cost, risk, and patient convenience (7). Clinically applicable non-invasive tests include radiological studies, elastography, and serum markers. These tests are not focused on exact staging of disease, but rather on dividing patients into categories of mild fibrosis (metavir stage 0 to 1) vs. significant fibrosis (metavir stage 2 or greater) and cirrhosis. They perform extremely well, as does biopsy, for excluding significant disease and for diagnosing cirrhosis with areas under the receiver operating characteristic curve of 0.85–0.95 (7). Cirrhosis can be diagnosed by standard radiological imaging showing features of cirrhosis such as splenomegaly, nodular liver, and varices. The ability of magnetic resonance imaging or ultrasound to diagnose cirrhosis or advanced fibrosis can be enhanced by elastography to measure liver stiffness. Elastography is not widely used in the United States, but many studies have shown a strong correlation of liver stiffness to the stage of liver fibrosis (8). Elastography can characterize patients as having either no or minimal portal fibrosis vs. bridging fibrosis and cirrhosis with a high area under the receiver operating characteristic curve of 0.95 (9). MR (magnetic resonance) elastography is also an excellent technique for determining liver stiffness, but is not widely available, and requires an MR scanner, significantly more time and expense (10). Ultrasound-based transient elastography such as FibroScan (Echosens, Paris, France) can be performed in the office in 5–10 min and gives the liver stiffness in kilopascals, which can then be used to inform the patient of the relative risk of significant fibrosis or cirrhosis.
1 Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. Correspondence: Nezam H. Afdhal, MD, Beth Israel Deaconess Medical Center, 110 Francis Street, Suite 8E, Boston, Massachusetts 02215, USA. E-mail:
[email protected] Received 15 July 2011; accepted 21 July 2011
© 2011 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
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Lai and Afdhal
Recently, two US studies have shown that elevated liver stiffness has been associated with both the presence of esophageal varices and an increased risk of adverse clinical outcomes over a 3-year period (11,12). In this current issue of American Journal of Gastroenterology, Rizzo et al. present their data for a type of ultrasound-based elastography, acoustic radiation force impulse (ARFI) elastography. As with Fibroscan, ARFI is performed on fasting patients using a non-invasive probe. While FibroScan sends a low-frequency elastic wave, ARFI uses a focused high-frequency ultrasonic beam to produce a mechanical deformation at the focal point of the beam. The velocity of the shear-wave triggered by this mechanical deformation is a measure of liver stiffness and fibrosis. The authors do not explain whether ARFI needs to be performed by a trained radiologist or can be done in the office by the hepatologist. They found ARFI to have a good yield, to be reproducible, and to be accurate for staging intermediate and advanced classes of liver fibrosis. The AUROC for ARFI was 0.86 for predicting metavir fibrosis stage 2 or higher, 0.94 for predicting stage 3 or higher, and 0.89 for predicting cirrhosis, compared with 0.78, 0.83, and 0.80 for FibroScan, respectively. While two previous studies did not find any significant differences between transient elastography and ARFI (13,14), Rizzo et al. found ARFI to have a significantly higher discriminatory capacity than FibroScan for intermediate stages of fibrosis. The question remains whether distinguishing between the intermediate stages have clinical relevance as therapy improves for HCV. Serological tests for staging liver disease are widely available in the United States and can be useful in clinical decision making (7). Like the radiographic studies and elastography, these tests can be used to determine the probability of no or mild fibrosis from advanced disease and cirrhosis. HepaScore (Quest Diagnostics, Madison, NJ) and FibroSure (Biopredictive, Paris, France) are commercially available tests, which use a linear scale that correlates with the stage of fibrosis (15). Each test measures multiple serum fibrosis markers and calculates a score, using a mathematical algorithm, to determine the probability of disease. These tests are particularly useful when exact staging of the disease is not needed. Clinical scenarios where these tests might be used include (i) a young patient with HCV and no clinical risk factors for advanced fibrosis and (ii) a patient who has clinical or radiological features of cirrhosis. The non-invasive serologic tests would confirm either mild disease in scenario 1 or cirrhosis in scenario 2. Improvement in HCV sustained viral response rates, particularly for genotype 1 disease, has become a reality and is only likely to further improve with many of the new direct acting antivirals currently under clinical investigation. With the Food and Drug Administration approval of telapravir and bocepravir and the availability of multiple non-invasive tests of liver fibrosis, we anticipate seeing a decreasing need for liver biopsies. With the higher cure rates seen with new treatments (16,17), differentiating between metavir fibrosis stage 1 and stage 2 may not be clinically relevant as you would likely treat the patient regardless of the disease stage. Non-invasive tests of fibrosis can be used to distinguish between mild disease and advanced fibrosis or cirrhosis in treatment-naive HCV patients who are candidates for treatment. Factors that will be important in determining which non-invasive test include expense, accuracy, as The American Journal of GASTROENTEROLOGY
well as convenience. Point-of-contact tests, which are easy to perform, are attractive as the results during that visit can help with clinical decision making at the time of the visit. ARFI looks to be promising as such a test but will need validation in larger cohorts and in US populations. It would also be important to know how much training is needed for an operator to be proficient. In summary, staging of liver fibrosis can now be performed with a variety of non-invasive tests. As more well-validated noninvasive tests for staging fibrosis become widely available and we have better treatments for HCV, the overall need for liver biopsy for clinical decision making will regress, making clinical care safer and more convenient for patients. CONFLICT OF INTEREST
Guarantor of the article: Nezam H. Afdhal, MD. Specific author contributions: Planned and involved in the writing of the manuscript: Michelle Lai and Nezam H. Afdhal. Financial support: None. Potential competing interests: Afdhal is a consultant for Quest (makers of Hepascore) and investigator for EchoSens (manufacturers of the FibroScan). REFERENCES 1. Rizzo L et al. Comparison of transient elastography (TE) and acoustic radiation force impulse (ARFI) for non-invasive staging of liver fibrosis in patients with chronic hepatitis C. Am J Gastroenterol 2011;106:2112–20 (this issue). 2. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371:838–51. 3. Bedossa P. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994;20 (1 Pt 1): 15–20. 4. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–57. 5. Goldin RD, Goldin JG, Burt AD et al. Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis. J Hepatol 1996;25:649–54. 6. Regev A, Berho M, Jeffers LJ et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614–8. 7. Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008;134:1670–81. 8. Friedrich-Rust M, Ong MF, Martens S et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960–74. 9. Cohen EB, Afdhal NH. Ultrasound-based hepatic elastography: origins, limitations, and applications. J Clin Gastroenterol 2010;44:637–45. 10. Talwalkar JA, Yin M, Fidler JL et al. Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology 2008;47:332–42. 11. Klibansky DA et al. Transient elastography for predicting clinical outcomes in patients with chronic liver disease. J Viral Hepat 2011; advance online publication, 1 July 2011. 12. Pritchett S, Cardenas A, Manning D et al. The optimal cut-off for predicting large oesophageal varices using transient elastography is disease specific. J Viral Hepat 2011;18:e75–80. 13. Goertz RS, Zopf Y, Jugl V et al. Measurement of liver elasticity with acoustic radiation force impulse (ARFI) technology: an alternative noninvasive method for staging liver fibrosis in viral hepatitis. Ultraschall Med 2010;31:151–5. 14. Sporea I, Sirli RL, Deleanu A et al. Acoustic radiation force impulse elastography as compared to transient elastography and liver biopsy in patients with chronic hepatopathies. Ultraschall Med 2011;32 (Suppl 1): S46–52. 15. Becker L, Salameh W, Sferruzza A et al. Validation of hepascore, compared with simple indices of fibrosis, in patients with chronic hepatitis C virus infection in United States. Clin Gastroenterol Hepatol 2009;7:696–701. 16. Jacobson IM, McHutchison JG, Dusheiko G et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405–16. 17. Poordad F, McCone J Jr, Bacon BR et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195–206.
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