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Liver Biopsy vs Non-Invasive Blood Tests in HCV/HBV
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Staging Liver Fibrosis: Time to Abandon Liver Biopsy?
August 07, 2005
Nezam H. Afdhal, MD
Chief of Hepatology
Beth Israel Deaconess Medical Center
Associate Professor of Medicine
Harvard Medical School
http://clinicaloptions.com/hep/ev/2005_ 6.asp
Additional reading referred to in article by Afdahl:
Noninvasive markers of hepatic fibrosis: Are they ready for prime time in the management of HIV/HCV co_ infected patients? _ (06/23/05)
http://www.natap.org/2005/HCV/062305_02.htm
Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT_ C cohort (08/05)
http://www.natap.org/2005/HCV/072105_09.htm
The established gold standard for the evaluation of liver disease has traditionally been a percutaneous liver biopsy. Liver biopsy is used predominantly for the diagnosis, prognosis, and staging of liver disease. Despite improvements in serologic diagnostic tests for liver disease, a biopsy is often still indicated to make the diagnosis of many forms of liver disease. Biopsy is also useful for determining prognosis, usually by confirming the presence or absence of cirrhosis. More recently, biopsy has been used for staging fibrosis in viral hepatitis and for decision analysis as to the need for treatment. Many treatment algorithms recommend treatment for patients with septal fibrosis or greater (≥ METAVIR stage 2). Improvement in either tolerability or efficacy of therapy could easily alter this current treatment paradigm, increasing physician and patient acceptability of therapy and reducing the need for liver biopsy.
Liver biopsy is rarely associated with severe complications in this era of ultrasound guidance or marking, and bleeding is rare (1:10,000 biopsies).[1] The major issues with biopsy are cost (approximately $2200) and patient acceptability and anxiety. In addition, recent studies have suggested that biopsy is only about 80% accurate in the staging of liver fibrosis and may even miss advanced fibrosis or cirrhosis in 30% of patients. The factors associated with the inaccuracy of biopsy include the heterogeneous nature of liver disease, the relatively small size of a biopsy compared to the size of the liver, and the experience of the pathologist. This has led to the concept that a liver biopsy should be at least 25 mm in length to reduce the sampling error.[2] Although this is a noble aim pathologically, it remains a clinical rarity, with only 20% of liver biopsies even approaching this length.
These limitations of biopsy have led clinical investigators to study alternative methods to stage liver disease. Noninvasive serum biomarkers are the most widely used alternative to liver biopsy and have recently been reviewed.[3] There are 2 major types of biomarker tests, those that use clinical variables to stage fibrosis and those that use extracellular matrix (ECM) markers.[4,5] There are advocates of specific tests, but overall the performance characteristics of all these tests are relatively similar.
The accuracy of a test is often given as the area under the curve (AUC) of the receiver operator characteristic (ROC). A perfect test with a 100% sensitivity and specificity would have an AUC of 1.0. The majority of proposed biomarker tests—and in particular, those available for use in clinical practice—have an AUC of between 0.80_ 0.85, not for staging disease, but for differentiating mild from (F0/F1) from significant fibrosis (F2_ F4). Since the biomarker is validated against the biopsy, and the accuracy of the biopsy is only 80%, it is probably statistically impossible for a biomarker to perform any better for staging fibrosis. Interestingly, the performance of biomarkers is superior at the extremes of disease; the indeterminate results occur when patients have F1/2 disease. This is not surprising, since these stages are relatively artificial separations of a spectrum of a dynamic disease process.
An alternative method for staging liver disease is to measure liver stiffness or elasticity using a FibroScan.[6] The principle is relatively simple and involves measuring the shear velocity of a 50 mHZ wave propagated through a 2_ 5 cm segment of the liver, and converting this into a stiffness value in kilopascals (kPA). The diagnostic accuracy of the test is similar overall to that reported for biomarkers, but it is probably better in diagnosing cirrhosis, with an AUC of 0.95. The test is simple and the results readily available, but the machine is still investigational in the United States and relatively expensive. Combining a FibroScan measurement with biomarkers may increase the accuracy of both tests.[7]
What can we recommend at the present time? Certainly, when the diagnosis is in doubt, a liver biopsy remains the gold standard (just make sure it is an adequate biopsy!) However, when the issue is staging of fibrosis for either treatment decision or exclusion of cirrhosis, biomarkers and noninvasive tests represent a valid initial alternative. If the biomarkers are clearly indicative of mild or advanced disease, no further evaluation is necessary, and where they are equivocal, a biopsy can subsequently be performed. Eventually one could even anticipate following patients on an annual basis with biomarkers and stiffness scans to follow the progression or regression of disease. It is not yet time to abandon liver biopsy for disease staging, but the lifeboats are out and the sharks are circling.
References
1. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001;344:495_ 500.
2. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449_ 1457.
3. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol. 2004;99:1160_ 1174.
4. Imbert_ Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069_ 1075.
5. Patel K, Gordon SC, Jacobson I, Hezode C, Oh E, Smith KM, Pawlotsky JM, McHutchison JG. Evaluation of a panel of non_ invasive serum markers to differentiate mild from moderate_ to_ advanced liver fibrosis in chronic hepatitis C patients. J Hepatol. 2004;41:935_ 942.
6. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705_ 1713.
7. Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, De Ledinghen V. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343_ 350.
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