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The March Toward Elastography for Assessing Fibrosis in HCV

There are a number of ways to assess fibrosis in HCV, but none are perfect. The long-time mainstay of measuring fibrosis — liver biopsy — may eventually fall out of fashion in the wake of advances in noninvasive measures. The clinical community has been seeking its replacement for two decades, and has largely turned to imaging techniques. Magnetic resonance and transient ultrasound elastography have become the twin pillars of the field. HCV Next spoke with a handful of experts regarding elastography, and it became clear that addressing serum biomarkers and other scoring systems along with ongoing use of biopsy is necessary. Each method comes with drawbacks. The arguments against these various non-invasive ways of assessing fibrosis range from cost, to small sample size, to limited ability to view the liver in its entirety.

Richard L. Ehman, MD, professor of radiology and Blanche R. & Richard J. Erlanger Professor of Medical Research at the Mayo Clinic, shared the basics in an interview with HCV Next. “The main problem with biopsy is that you only sample a small section of the liver,” he said. “If the fibrosis in the liver is not homogeneous then that small sample may overestimate or underestimate the overall level of fibrosis.”

He added that different pathologists may evaluate the same biopsy specimen differently. “Plus, liver biopsy is expensive and uncomfortable for the patient,” he said.

In the mid-1990s, researchers developed a Magnetic Resonance Imaging (MRI) technique that can visualize micron-level mechanical waves propagating through soft tissue, according to Ehman. This led to development of a technology called Magnetic Resonance Elastography (MRE), which uses mechanical vibrations and MRI to generate images showing the stiffness of tissues in the body. In parallel, researchers have developed similar techniques using ultrasound technology. The most common of these devices is known as Fibroscan (Echosens).

“These are techniques for measuring the stiffness of liver. A healthy liver is very soft, while cirrhotic liver is very hard,” Ehman said. “By measuring the stiffness of liver tissue, we can detect fibrosis and estimate its severity. The importance of these techniques is that most patients with liver fibrosis do not have any anatomic changes that could be detected with conventional imaging techniques until the disease is very advanced.”

Clinicians in the U.S. rely heavily on magnetic resonance elastography (MRE), whereas various forms of ultrasound elastography are used abroad, according to SimonTaylor-Robinson, MD, PhD, clinical consul for the Faculty of Medicine at Imperial College of London. “Ultrasound contrast agents are the gold standard outside the U.S., largely because access to MR machines is less common in other parts of the world,” he said. “In the U.S., people tend not to use ultrasound.”

Even in the U.S., though, there is great variability in access to technology and approaches to assessing fibrosis, Zarine Shah, MD, MBBS, assistant professor in the Division of Abdominal Imaging, Department of Radiology at The Ohio State University Wexler Medical Center, said in an interview. “At Ohio State, we are familiar with both techniques — MR elastography and transient ultrasound elastography,” she said. “Patients with a higher clinical concern — maybe a tumor or portal hypertension — are coming in for a comprehensive evaluation, including MR elastography. But ultrasound-based elastography techniques are much more available in community centers. That seems to be the primary method outside of major academic centers.”

It is not hard to imagine, though, a time when clinicians in the U.S., and even outside the U.S., will reach that goal of accurately and consistently assessing that tricky middle stage of fibrosis. It is with this in mind that HCV Next hopes to provide an overview of where we stand in measuring liver stiffness today.

Magnetic Resonance Elastography

“We have been using MRE at the Mayo Clinic since 2007,” Ehman said. “After the FDA approved this technology in 2009, GE, Philips and Siemens produced MRI scanners that have been made available all over the world. There are about 600 centers around the world that have this technology.”

Shah acknowledged, though, that MRE is an involved procedure. “The patient is in the MRI scanner,” she said. “We place a drum or instrument on the upper quarter of the abdominal wall that creates sound waves that travel through the liver. This shows how the liver responds and how elastic it is.”

The measurement comes with an image, which is one significant advantage of this approach. “Another advantage is that we get a really large sample, a much better representation of what is really going on in the liver,” Shah said. “This procedure is not inhibited by ascites or the thickness of the abdominal wall, so we can use it in larger patients.”

MRI technology also offers advantages beyond measuring stiffness of the liver, according to Shah. “We can look at focal conditions in the liver, including tumors and underlying causes of cancers.”

Shah also discussed emerging MR technology to assess fat in the liver and how this may have implications for primary care physicians and hepatologists. “We see so many patients with underlying obesity and diabetes, conditions that lead to fatty liver disease,” she said. “We can use MR to diagnose NASH and NAFLD and then follow up to see how they improve with treatment. If we can use MRI fat quantification technology and measure the stiffness of the liver with MRI elastography, we can triage patients with simple fatty liver and those with fatty liver with inflammation (NAFLD). Those with fatty liver but no increased stiffness could then be treated by primary care providers. Patients with advanced disease (NAFLD) need subspecialty care with hepatology. This can free up hours for busy hepatologists.”

A key disadvantage of MRE over ultrasound techniques is that the procedure is more time consuming and expensive. “Also, patients who have non-MRI compatible cardiac pacemakers, aneurysm clips or other devices that are not MRI safe are not candidates for MRI,” she said.

Perhaps the biggest obstacle is cost and difficulty securing coverage, according to Shah. “There is currently not a code available to charge a patient for elastography,” she said. “This makes it challenging for the clinicians to order these studies, as this procedure may not be reimbursed by insurance.”

That said, MRE is effective. Ehman was a researcher on a study (Yin et al.) that retrospectively assessed the technical success rate and diagnostic performance of MRE. The analysis included 1,377 consecutive procedures performed in 1,287 patients from 2007 to 2010. Results indicated that hepatic MRE was associated with a success rate of 94.4%, observed in 1,300 of 1,377 cases. The researchers also reported that elastography yielded reproducible measurements (P < .0001) with a complex patient profile and multiple interpreters. No significant association was reported between BMI and success rate.

The study also included 289 patients who underwent liver biopsy within a year of undergoing elastography. Patients in that group with F3 or F4 fibrosis had significantly higher mean liver stiffness than those with F0 to F2 fibrosis (5.93 kPa ± 2.31 [standard deviation] vs. 3.35 kPa ± 1.44; P < .0001). It was reported that many factors other than fibrosis may be associated with liver stiffness, including the cause of fibrosis (viral HCV vs. NAFLD; P = .025), inflammation (severe vs. mild to moderate; P = .03) and hepatic metabolic and synthetic function (no fibrosis vs. intermediate fibrosis; P .01), according to the results. “In [a] general clinical practice environment, hepatic MRE is a robust imaging method with a high success rate in a broad spectrum of patients,” the researchers concluded. “It also shows the complex association between liver stiffness and hepatic pathophysiology.”

“This article describes our experience with clinical use of this technology since 2007,” Ehman said. “We can take a number of broad observations from these results, including that the rate of technical failure is low.”

Transient Ultrasound Elastography

Taylor-Robinson noted that a number of manufacturers, including ElastoPQ from Philips in the Netherlands and acoustic radiation force impulse (ARFI) elastography from Siemens in Germany, make similar devices as the FibroScan. “They resonate the liver at a different frequency and are not exactly the same as FibroScan, but the net result is the same, the outcomes are the same,” he said. “They have slightly different bells and whistles but they are still measuring liver stiffness.”

A typical scan will measure the thickness of a space 6 inches below the surface of the skin, according to Ehman. This measurement is taken 10 times.

“The FibroScan equipment does not have an imaging capability to indicate exactly where the measurement is obtained,” he said. “The newer ultrasound-based elastography technology provides cross-sectional imaging, as well as stiffness measurements.”

The addition of the image has proven of great importance, according to Ehman. “The image with ARFI is an improvement over FibroScan,” he said. “It is still a spot measurement, but you can at least see where it is being made.”

The widespread commercial availability of ultrasound technology is a key advantage, according to Shah. “Also, it is a quick technique, relatively less expensive, and can be done without the screening measures needed for MRI safety,” she said.

Taylor-Robinson noted that ultrasound can also measure fat in the liver. “FibroScan measures fat with the CAP, or continuous attenuation parameter,” he said. “This measures diffraction across the liver. The diffraction is scattered more if there is more fat. The angles radiate differently. This is actually a surrogate measure of fat.”

An important disadvantage of ultrasound is that it can be difficult to obtain a reading in overweight or obese patients. “The most accurate reading is taken at least 2 cm deep to the surface of the liver,” Shah said. “If you have a larger patient, it’s difficult to get a reading at adequate depth. The size of the patient can be a prohibiting factor.”

Readings can also be compromised if there are ascites or fluid in the liver, according to Shah. She added that another disadvantage is that although it can measure a liver that is very soft or very stiff, it does not provide more nuanced findings. “This technology is not good at grading the level of fibrosis,” she said.

MR vs. Transient Elastography

Ehman believes that each of the techniques has a place in medical care. “They are just different ways of achieving the same goal,” he said. However, he stressed that ultrasound-based techniques have been associated with about a 15% failure rate, whereas MRI failure is 5% or less. “Essentially all of the literature shows that MRE has a higher diagnostic performance.

“That said, there are many situations where an ultrasound-based elastography technique may be very appropriate,” Ehman said. “For example, it might be used in an HIV clinic as a screening tool with low cost.”

In terms of comparisons, magnetic resonance will show a larger portion of the liver than ultrasound, while ultrasound will show a larger portion than a biopsy. “As you show more of the liver, the diagnosis gets more accurate,” Ehman said.

Portability is another advantage of the ultrasound machine, according to Ehman. “However, cost is a more complex issue than it would seem on the surface,” he said. “It will cost more to buy a FibroScan machine than it will to upgrade an MRI machine.” “Plus, an MRI machine has more capabilities. You can rule out portal hypertension and cancer, for example. It just takes a bit more imaging time to include those capabilities.”

“Something else to consider is that if you have a FibroScan, there is a standard billing code,” he added.

Serum Biomarkers

There are a number of scoring systems that clinicians use independently or in conjunction with imaging techniques to paint a clearer portrait of fibrosis. The Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) model is calculated using the patient’s aspartate aminotransferase level and platelet count, along with the upper limit of normal of aspartate aminotransferase level. Like many other scoring systems, this model is not completely accurate in differentiating between intermediate from mild or severe fibrosis. “This is a good, cheap marker that is being used in the developing world,” Taylor-Robinson said.

The Fibrosis-4 score (FIB-4) is calculated using the patient’s age, AST, alanine aminotransferase, and platelet count. This, too, requires another measure — ideally an image — to be accurate. The FibroIndex uses the patient’s AST, platelet count and gamma globulin. This method has been associated with high specificity for mild or significant fibrosis, but has low sensitivity. “These are relatively simple indices,” Ehman said.

For the Forns Index, clinicians calculate the patient’s age, gamma-glutamyltransferase (GGT), cholesterol and platelet counts. Although this method has good predictive value in selecting patients who are not at high risk for significant fibrosis, it is unreliable in predicting advanced fibrosis or cirrhosis. It may predict response to therapy. Also, this method is not useful in patients with genotype 3 HCV.

Next is the HepaScore — also known as the FibroScore — that includes the patient’s age, sex, total bilirubin, GGT, alpha-2-macroglobulin and hyaluronic acid levels. This can be used to exclude significant fibrosis but may not be useful in predicting cirrhosis.

The enhanced liver fibrosis, or ELF test, is in development by Siemens and measures hyaluronic acid, procollagen III amino terminal peptide and tissue inhibitor of metalloproteinase 1.

“There is always work going on in this area,” Taylor-Robinson said. “People are looking at a number of different markers. There are biomarkers in the urine that signify cirrhosis, for example.”

To that point, Trovato and colleagues described emerging tools in assessing fibrosis in HCV, which included a cross-section of interventions, from elastography to in vitro urinary nuclear MRI. “Some of the techniques and tests described are already suitable for more widespread clinical application, as is the case with ultrasound-based liver diagnostics, but others, such as urinary metabonomics, requires a period of critical evaluation or development to take them from the research arena to clinical practice,” they wrote.

“Magnetic resonance spectroscopy in vivo is not a standard, everyday diagnostic technique,” Taylor-Robinson said. “It is primarily used for looking at underlying mechanisms at the moment. This is currently in the domain of research. We are many years from using it in primary care.”

El-Asrar and colleagues evaluated serum YKL-40, an inflammatory glycoprotein involved in endothelial dysfunction, in a cohort of 50 children and adolescents with beta-thalassemia major. They compared these findings with serum YKL-40 in 35 healthy controls, with the aim of determining the relationship of this glycoprotein to liver stiffness as assessed by elastography, markers of hemolysis, iron overload and various hemolysis-associated complications.

The results indicated a correlation between YKL-40 and liver stiffness, with the degree most pronounced among patients with F4 fibrosis (P < .001). YKL-40 also showed a positive correlation with transfusion index, ALT, lactate dehydrogenase, serum ferritin and liver iron concentration. “YKL-40 is a promising marker of cardiovascular disease and liver siderosis in [beta-thalassemia major] patients,” the researchers concluded. “The combination of YKL-40 and [transient elastography] provides a reliable method to assess hepatic fibrosis in young [beta-thalassemia major] patients.”

“In general, this is an area that is unfolding,” Ehman said. “There is a place for all of these indices, even in the North American population where elastography techniques are leading the charge.”

For Taylor-Robinson, the ultimate goal would be a panel of markers that are 100% discriminatory. “There have been a lot of papers exploring this, but nothing has been fully validated,” he said.

Other Comparisons

Much of the literature in this field involves comparing and combining various imaging modalities and scoring systems. Dyvorne and colleagues prospectively compared MRI to transient elastography and serum markers for the detection of fibrosis in a cohort of 60 patients with liver disease. MRE yielded the strongest correlation with the stage of fibrosis (r = 0.66; P < .001), inflammation grade (r = 0.52; P < .001) and collagen content (r = 0.53; P = .036). For the detection of F2 to F4 fibrosis, MRE was most effective, followed by transient elastography, dynamic contrast-enhanced MRI, diffusion weighted MRI and APRI score. MRE was also most effective in detecting F3 to F4 fibrosis.

“You have to think about it in terms of what you are looking at,” Shah said. “Can you assess advanced fibrosis or not? Ultrasound does a pretty good job of it, but can it provide level of detail? It just doesn’t match up with MRI in that scenario.”

Cabibi and colleagues studied correlations between histochemical stainings and transient elastography in assessing fibrosis in a cohort of 111 consecutive patients with chronic HCV. The staining methods included Masson’s trichrome, Sirius Red and orcein stainings. The three staining methods demonstrated concordant results for 89.6% of cases in staging HCV. This result included no significant difference in semiquantitative and quantitative evaluations of fibrosis, according to the findings. Transient elastography findings were concordant with orcein levels in 86.5% of patients and concordant with Masson’s trichrome and Sirius Red in 77.5% (P < .001). The researchers concluded that the three staining methods are almost concordant with transient elastography, but that when there is discord, orcein staining is the closest to the ultrasound technique. “This suggests that elastic fibers play a more important role than reticular or collagenous ones in determining stiffness values in [HCV],” they wrote.

The Future of Liver Biopsy

All of this raises the question of whether biopsy has been left behind, or will be left behind. “The rates of biopsy have gone down considerably, but there is still a need for it,” Ehman said. “Typically it is used when other tests don’t provide a clear answer, when there is still some question as to what is going on.”

Shah took a slightly different stance. “There is so much strong evidence moving in the direction of [magnetic resonance] and ultrasound elastography,” she said. “Let’s not biopsy patients if we have a way around it.”

She added that the cost of biopsy is comparable to the cost of MRI. “But this is an invasive procedure with a whole list of complications, so you have to expect some downstream costs associated with biopsy,” she said.

Kucharska and colleagues explored avenues beyond biopsy for assessing liver disease in hemophiliacs who acquired the disease in the 1980s. “It is therefore highly likely that many of them, more than 20 years after the infection, have developed advanced liver disease,” they wrote. “Until recently, in order to assess its severity, it was necessary to perform a liver biopsy.” They described the developments in noninvasive measures of this disease, including elastography and algorithms based on blood parameters. They concluded that the ease of use of these methods can help direct patients efficiently into an appropriate course of therapy.

“It is important to remember the ultimate goal of all of this intervention,” Taylor-Robinson said. “We are trying to achieve [sustained virologic response] in patients with HCV.”– by Rob Volansky

• References:
• Cabibi D, et al. Anal Cell Pathol (Amst). 2015; doi:10.1155/2015/431750.
• Dyvorne HA, et al. Liver Int. 2016; doi:10.1111/liv.13058.
• El Asrar MA, et al. Blood Cells Mol Dis. 2016; doi:10.1016/j.bcmd.2015.09.006.
• Kucharska M, et al. Adv Clin Exp Med. 2015; doi:10.17219/acem/22913.
• Trovato FM, et al. World J Hepatol. 2015; doi:10.4254/wjh.v7.i26.2664.
• Yin M, et al. Radiology. 2016; doi:10.1148/radiol.2015142141.

• For more information:
• Richard L. Ehman, MD, can be reached at 200 First St. SW, Rochester, MN 55905; email: ehman.richard@mayo.edu.
• Zarine Shah, MD, MBBS, can be reached at 395 W. 12th Avenue, Room 476, Department of Radiology, Columbus, OH 43210; email: zarine.shah@osumc.edu.
• Simon Taylor-Robinson, MD PhD, can be reached at Department of Medicine, Faculty of Medicine, Imperial College London, 10th Floor QEQM Building, St. Mary’s Hospital, Praed Street, London W2 1NY; email: s.taylor-robinson@imperial.ac.uk.

Disclosures: Ehman serves as president and CEO of Resoundant Inc., a company established by the Mayo Clinic to produce MRE technology available to patients around the world. The Mayo Clinic and Ehman have intellectual property rights and financial interest in the technology. Shah and Taylor-Robinson report no relevant financial disclosures.