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The Next Wave: Noninvasive Alternatives to Assess Fibrosis
Imaging modalities and serum markers challenge liver biopsy as the gold standard
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Liver biopsy has been called into question as the gold standard for assessing liver fibrosis, largely due to the advent of novel imaging techniques and serum marker calculations. A number of noninvasive methods have gained traction worldwide and approval for use in the United States. However, whether these modalities can replace liver biopsy as the definitive approach to determining the extent of fibrosis — and whether it even matters — is currently up for debate.
Liver biopsy is under some degree of re-evaluation, Nezam H. Afdhal, MD, director of hepatology at Beth Israel Deaconess Medical Center, professor of medicine at Harvard Medicine School and HCV Next Editorial Board member, said during a presentation at Digestive Disease Week 2014.
Nezam H. Afdhal
“Clinical needs have changed over the last 10 to 20 years,” Afdhal said. “Better technologies for evaluation of liver fibrosis have been developed. It’s not just that liver biopsy is being done less frequently; we have changed the way we practice hepatology.”
Changing Needs, New Advances
Liver biopsy is “alive and well” when it is used for diagnostic purposes, Afdhal said. In more cases liver biopsy is done for staging the degree of fibrosis in the liver. However, there are a number of alternative techniques to liver biopsy that can help the physician do this.
Changing needs and new technologies have yielded alternative options such as FibroScan elastography, transient magnetic resonance (MR) elastography and acoustic radiation force impulse (ARFI). Beyond these imaging techniques, serum-based tests have also gained clinical foothold, including the aspartate aminotransferase-to-platelet ratio index (APRI) and FibroSure, known as FibroTest outside of the United States. FIB-4, HepaScore, FibroIndex and Forns index are just a few of the other serum markers that clinicians are employing.
Traditionally, liver biopsy has been used as a diagnostic and prognostic tool for the treatment of hepatitis C virus in the interferon-only era. Many clinicians were also using it for staging fibrosis to rule out a need for use of interferon due to its adverse effects, according to Afdhal. “Today, [this use] is not as relevant because the newer HCV treatments have very high cure rates, favorable tolerability and [a favorable] side effect profile. Now, the reason to do a liver biopsy to make a treatment decision is somewhat less urgent.”
Stuart C. Gordon
Despite recent advances, the clinical community has raised two important issues about the use of biopsy to assess fibrosis in HCV. Stuart C. Gordon, MD, professor of medicine and director of hepatology at Henry Ford Hospital in Detroit, raised the first concern. “Although the various biomarkers and imaging modalities that assess for fibrosis were developed with biopsy as the gold standard, there are multiple inherent limitations of a liver biopsy itself,” he said.
Such limitations include pain or bleeding, inaccurate fibrosis staging from sample errors, variability in interpretation, and a cost that ranges from about $2,000 to $3,000 in the United States.
“These limitations seriously challenge the notion that this is the best way to establish the extent of hepatic fibrosis in patients with HCV,” Gordon said.
Another important issue surrounds the effect of assessing fibrosis on treatment decisions made today.
“Frankly, I don’t think fibrosis is as important as it used to be,” Douglas T. Dieterich, MD, professor of medicine in the division of liver disease and director of outpatient hepatology at the Icahn School of Medicine at Mount Sinai, and HCV Next Editorial Board member, said in an interview. “We have been triaging patients based on fibrosis. But, when the Gilead and AbbVie fixed-dose combinations hit the market in the near future, fibrosis testing will be much less important. By the following year, fibrosis staging will be fading away as a reason to treat or not to treat.”
Douglas T. Dieterich
According to William D. Carey, MD, from the Transplant Center and Digestive Disease Institute at Cleveland Clinic and director of the Center for Continuing Education at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University: “Degree of fibrosis is not as important today as it was 5 years ago. We can now treat all of our patients with HCV really well. It is possible that 5 to 10 years from now, treating patients with fibrosis will not be too different from treating patients without fibrosis. This is a moving target.”
Until a time when optimal therapies are widely accessible and the perfect noninvasive method for assessing fibrosis reveals itself — or perhaps until the need for assessing fibrosis is truly eliminated — experts must continue to debate the present and future state of liver biopsy.
The Future of Liver Biopsy
Carey said he has performed a considerable amount of research on noninvasive methods for assessing fibrosis, and all of that research has yielded a question: “When HCV was first identified, we were doing a biopsy in every patient. Then we asked ourselves, ‘how useful is the biopsy?’”
In a study by Carey and colleagues, about 27% of patients had advanced fibrosis or cirrhosis. He said that in only a small percentage would then-available blood tests have predicted this degree of scarring. “Our conclusion was that biopsy was necessary in staging HCV and proving cirrhosis.”
However, in the past 5 years, serum and imaging techniques have filled some of those gaps, he said. “Will we completely eliminate the need for biopsy? I think not, but it will be complemented by these other approaches.”
Gordon agreed. “For the standard HCV patient, liver biopsy may become obsolete in many cases because the presence of cirrhosis can largely be predicted noninvasively,” he said. “Examples where biopsy will remain useful in HCV settings include the post-transplant patient, where rejection must be excluded, or in concomitant liver disease such as autoimmune disease.”
Regardless of how the field develops, liver biopsy involves the greatest amount of training, cost and, above all, risk, according to Gordon. These factors may play a role. “The serum biomarkers involve a blood draw that awaits results from the lab or calculation of simple parameters,” he said. “Imaging techniques involve utilization of the imaging suite and its trained personnel as well as a radiologist’s expertise, with varying degrees of costs depending on the specific imaging modality used. But it is anticipated that transient elastography will gradually replace the need for invasive liver biopsies in patients with HCV.”
Imaging Modalities
Noninvasive imaging techniques are gaining popularity for the measurement of liver stiffness.
One of the most promising new devices is the FibroScan (Echosens), which received 510(k) clearance from the FDA in 2013. Based on ultrasound-based vibration-controlled transient elastography, FibroScan assesses liver shear wave speed, expressed in meters per second, and equivalent stiffness, expressed in kilopascal, at 50 Hz. A large pool of research supports the use of FibroScan for this purpose. The test produces highly sensitive results and is fast, simple, noninvasive and painless for patients. Initially introduced in the European market in 2003, FibroScan pioneered the quantitative elastography medical field. It is currently available in more than 70 countries worldwide.
“Unlike hepatic ultrasound and unlike MR elastography, no imaging of the liver is involved with the FibroScan. Instead, there is the mechanical passage of a sound wave across the liver, and the device measures the speed with which that sound wave traverses the liver. Graphics are created by the shear wave generated, and these graphics are interpreted using a minimum of 10 valid readings, with the final score representing the median of those 10. “Because FibroScan samples a larger proportion of the liver than that which could be obtained in liver biopsy, the transient elastography stiffness score may, in fact, better reflect liver fibrosis than a random biopsy,” Gordon said.
One drawback of the FibroScan is that it cannot be used in every patient, such as those who have ascites, are morbidly obese or have large amounts of chest wall fat, as the test may not be able to be performed or the results may be unreliable. However, Echosens extended the limits of the FibroScan to obese patients when it launched an XL probe, which has a 2.5 MHz ultrasonic transducer, new electrodynamic transducer and adapted algorithm to perform deeper calculation between 35 mm and 75 mm. Another reason for potential failure is operator inexperience. Afdhal said the recommendation is that 50 to 100 FibroScan procedures should be done as part of training, noting that “it is not a difficult test once you are used to using the device.”
MR elastography is a highly sensitive method that uses low-frequency mechanical waves to assess liver stiffness and images the entire liver. However, a downside is that this technique requires patients to undergo an MRI and, thus, more time and expense in contrast to the FibroScan, which is portable and can be performed at the point of care. Another method is ARFI, an ultrasound-based modality that uses a high-frequency ultrasonic beam to produce a mechanical deformation at the focal point of the beam. Data on both tests have demonstrated a good yield, reproducibility and accuracy in staging classes of liver fibrosis.
Serum Markers
The arguments in favor of utilizing serum markers are relatively straightforward. These approaches are cheap and require only measurements and calculations.
Papastergiou and colleagues provided an overview of the calculations associated with each approach, along with opinions about their relative utility. APRI is calculated by dividing the aspartate aminotransferase (AST) by 35; then dividing that number by the platelet count; then multiplying this number by 100.
The other most accepted method, the FibroSure indirect serum marker panel, utilizes a proprietary algorithm that includes patient age and sex, along with a composite of six biochemical markers associated with hepatic fibrosis: alpha-2-macroglobulin, haptoglobulin, gamma-glutamyl transferase (GGT), apolipoprotein A-I, total bilirubin and alanine aminotransferase (ALT), according to the researchers.
The FIB-4 score uses age, AST, ALT and platelet counts. Papastergiou and colleagues said although this method has demonstrated efficacy in excluding or confirming cirrhosis, its ability to discriminate fibrosis remains uncertain. The approach may have sensitivity in excluding significant fibrosis.
HepaScore, which is also known as FibroScore, includes the parameters of age, sex, total bilirubin, GGT, alpha-2-macroglobulin and hyaluronic acid levels. This method requires a more complicated calculation than some of the other methods but has demonstrated efficacy in excluding significant fibrosis, according to Papastergiou and colleagues. FibroIndex takes into account AST, platelet count and gamma globulin, and it may predict mild or significant fibrosis, albeit with low sensitivity, they wrote. The Forns index uses age, GGT, cholesterol and platelet counts. It may predict low risk for significant fibrosis but has not demonstrated reliability in predicting advanced fibrosis, according to the researchers.
The clinical community is not short of opinions about these biomarkers.
"All of these biomarkers involve calculation of an estimated fibrosis score using various blood tests that either reflect liver injury, such as enzyme levels, age, portal pressures (platelet counts), or elements of the fibrous matrix," Gordon said. "Scores such as FIB-4 are particularly valuable in large retrospective cohort studies wherein biopsy specimens may not be available but laboratory values are. This allows assessment of liver disease severity that might otherwise not be feasible."
Mitchell L. Shiffman, MD, director of the Liver Institute of Virginia in the Bon Secours Health System and HCV Next Editorial Board member, said for determining whether a patient has cirrhosis, FibroSure, FIB-4 and APRI are free and relatively simple with the appropriate laboratory data. "All of these modalities are excellent and correlate closely with biopsy in patients with none or minimal fibrosis," he said. "However, none of these modalities can reliably separate stage 1-3 fibrosis."
Mitchell L. Shiffman
Dieterich, however, said he has never been a "believer" of these tests. "There are so many, and they are mostly complicated. Also, they don’t give you a really solid number. They essentially answer yes or no, whether they’re cirrhosis or fibrosis. I can do that by looking at the platelet count. It is not clear to me why you would waste $500 for this."
Many available data are accordingly inconclusive.
Chinnaratha and colleagues conducted a study to predict outcomes in 406 patients by noninvasive fibrosis models. HepaScore and liver biopsy predicted overall and liver-related mortality, along with decompensation, whereas APRI and FIB-4 did not (P<.005). The researchers added that HepaScore was comparable to biopsy in terms of accuracy in predicting liver-related mortality.
Chou and colleagues investigated 172 studies for diagnostic accuracy. They found that platelet counts, age-platelet index, APRI and HepaScore demonstrated efficacy in identifying cirrhosis. When the strategies were directly compared, APRI was associated with a slightly lower area under the curve than the FibroTest for identifying fibrosis and a substantially higher area under the curve than the AST-ALT ratio in finding fibrosis or cirrhosis. "Many blood tests are moderately useful for identifying clinically significant fibrosis or cirrhosis in HCV-infected patients," the researchers concluded.
Benefits of a Combination Approach
Some experts believe that a combination approach is the best way to evaluate fibrosis in a patient with HCV.
“The optimal approach to evaluate fibrosis is with a combination of elastography and serum,” Afdhal told HCV Next .
Carey said for significant or severe fibrosis, a combination of APRI calculation sequenced with the FibroTest and FibroSure should provide an adequate definition of fibrosis.
However, usefulness of these tests aside, access is an issue. “Elastography is not commonly used right now because a lot of people do not have access to it. So instead, people are using serum markers,” Afdhal said.
Shiffman discussed another side of the issue. “All of the fibrosis markers and imaging techniques are excellent and closely correlate with liver biopsy at identifying patients with cirrhosis and patients with no fibrosis — the two ends of the spectrum,” he said. “But all of these modalities are less reliable and do not correlate well with biopsy in the middle, in patients with stage 1-3 fibrosis. None of these modalities can assess for other things in the liver biopsy tissue, degree of inflammation, bile duct injury, graft rejection post-transplant, iron overload, and so on. MR elastography has shown promise in possibly separating benign steatosis from nonalcoholic steatohepatitis, but the data are still not good.”
“One blood test alone isn’t going to be the best way,” Carey said. “We will need to continue to develop these sequential algorithms for fibrosis, largely because they are signifiers of cancer and other complications.”
Expectations Abound
Shiffman said he is confident that, in the future, many liver biopsies will be able to be replaced with any of the aforementioned noninvasive techniques.
However, “this is only if the only information you are looking for in the biopsy is fibrosis. These noninvasive techniques will not help diagnosing cholestatic liver disease, drug-induced liver disease, the severity of inflammation in autoimmune hepatitis, the severity of iron overload in a patient with hemochromatosis, and to differentiate benign steatosis from [nonalcoholic steatohepatitis].” For Dieterich, it is a matter of utilizing all of the available tools. “The more of them we can use, the better off we will be,” he said. “There are a million ways to measure fibrosis.”
“Liver biopsy is not yet dead, but it’s in the coffin,” Afdhal said. – by Rob Volansky
References:
Chinnaratha MA. Liver Int. 2014;34:720-7277.Chou R. Ann Intern Med. 2013;158:807-820.
Echosens. www.echosens.com. Accessed on May 8, 2014.
Ferraioli G. World J Gastroenterol. 2014;20:4787-4796.
Lai M. Am J Gastroenterol. 2011;106:2121-2122.
Pang JX. PLoS One. 2014;9:e95776.
Papastergiou V. Ann Gastroenterol. 2012;25:218-231.
For more information:
Nezam H. Afdhal, MD, can be reached at the Beth Israel Deaconess Medical Center Division of Gastroenterology/Liver Center, 110 Francis St., Suite 8E, Boston, MA 02215; email: nafdhal@caregroup.harvard.edu.William D. Carey, MD, can be reached at Cleveland Clinic Main Campus, Mail Code A-51, 9500 Euclid Ave., Cleveland, OH 44195; email: careyw@ccf.org.
Douglas T. Dieterich, MD, can be reached at Mount Sinai Hospital Department of Medicine – Liver Diseases, 5 E. 98th St., 11th Floor, New York, NY 10029; email: douglas.dieterich@mountsinai.org.
Stuart C. Gordon, MD, can be reached at Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202; email: sgordon3@hfhs.org.
Mitchell L. Shiffman, MD, can be reached at the Liver Institute of Virginia, Mary Immaculate Hospital, Medical Pavilion, 12720 McManus Blvd., Suite 313, Newport News, VA 23602; email: mitchell_shiffman@bshsi.org
Disclosures: Afdhal reports receiving research support within the last 2 years from AbbVie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen Therapeutics, Merck and Vertex, and serving as a consultant/advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead, GlaxoSmithKline, Janssen Therapeutics, Kadmon, Ligand, Medgenics, Merck, Novartis, Springbank and Vertex. Carey reports no relevant financial disclosures. Dieterich reports serving as a consultant or scientific advisor for AbbVie, Bristol-Myers Squibb, Gilead, Indenix, Janssen Therapeutics and Merck; he reports receiving grants or research support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen Therapeutics and Merck. Gordon reports associations with companies including AbbVie, Amgen, Bristol-Myers Squibb, CVS-Caremark, Exalenz, Gilead, GlaxoSmithKline and Merck. Shiffman reports relationships with AbbVie, Achillion, Bayer, Breckman-Colter, Bristol-Myers Squibb, Boehringer-Ingelheim, Gen-Probe, Gilead, GlaxoSmithKline, Intercept, Janssen Therapeutics, Lumena, Merck, Novartis, Roche/Genentech, Salix and Vertex.