Histologic assessment of liver disease has been a cornerstone of therapeutic decisions and predicting prognosis in chronic liver disease for much of modern hepatology. Although we still regard liver biopsy as the gold standard for assessment of injury, inflammation and fibrosis stage, its clinical application for chronic hepatitis C (HCV) has significantly decreased over the past decade. Non-invasive approaches for assessment of liver fibrosis have been under development over the same period, and now include various “biochemical” serum marker panels, or imaging modalities, which provide a “physical” measure of liver stiffness.1 These non-invasive tests certainly overcome the risks, and perhaps some of the limitations, associated with liver biopsy, but have diagnostic limitations that need to be considered when interpreting results.
From a historical perspective, the initial development of serum fibrosis marker panels in chronic HCV, (such as the proprietary FibroTest, BioPredictive, Paris, FR [HCV FibroSURE, LabCorp, Burlington, NC, in the U.S.], or the easily calculated nonproprietary AST-to-Platelet Ratio [APRI]), were based upon differentiating a broad fibrosis range (e.g. METAVIR F0-1 vs. F2-4).
The subsequent development of vibration-controlled transient elastography (FibroScan®, Echosens®, Paris, FR) provided a viable alternative method for differentiating these broad categories of fibrosis. Early studies showed us that biopsies could be avoided in most patients, if the presence of F2-F4 was the only information required to guide the decision to initiate 48 weeks of interferon-based therapy. The rapid evolution of simplified noninterferon direct acting antiviral therapeutic regimens, with high efficacy and tolerability among all HCV genotypes, suggests that the role of liver biopsy for accurate staging of disease prior to antiviral therapy is even more limited. There has been a steady decline in the use of diagnostic liver biopsy in chronic hepatitis C, as can be judged by the experience of any recent graduate from a gastroenterology fellowship. This has been paralleled by the increased availability, use and subsequent incorporation of noninvasive tests in chronic HCV clinical practice and society guidelines.2 The requirement for fibrosis staging prior to antiviral therapy approval by third-party payors, means that our routine narrative in everyday clinical practice now includes results from vibration-controlled transient elastography or serum fibrosis marker panel.
Following regulatory approval of transient elastography in the U.S. in 2013, there is increasing but not universal availability of this device.3 At our tertiary medical center in North Carolina, patients still travel significant distances for vibration-controlled transient elastography assessment. Other practical limitations that prevent point-of-care testing for all chronic HCV patients at their initial visit includes significant facility fees that often require prior authorization, and/or the absence of a dedicated technician or experienced provider. Quality measures are established for transient elastography, and require at least 10 validated measurements, a success rate (the ratio of valid measurements to the total number of measurements) of greater than 60 percent, and an interquartile range that reflects variations among liver stiffness measurements of less than 30 percent of the median value (interquartile range/liver stiffness measurement (IQR/LSM) less than or equal to 30 percent). Interpretation of the liver stiffness measurement must be in the context of these quality metrics.
In fact, prior studies have shown that the highest accuracy for fibrosis staging is obtained with the more stringent interquartile range/liver stiffness measurement less than or equal to 10 percent. Around 15 percent of results may be unreliable, and failure to obtain any liver stiffness measurement occurs in 3 percent of chronic HCV patients, mostly due to obesity or operator inexperience (less than 500 examinations). Transient elastography results indicating IQR/LSM greater than 30 percent in conjunction with liver stiffness measurement greater than or equal to 7.1 kPa are particularly unreliable.
In clinical practice, liver stiffness measurement readings can still be obtained in most patients, so quality measures are often overlooked. This important limitation is perhaps not always appreciated by the requesting provider, and is rarely documented clearly in the main narrative. By obtaining liver stiffness measurements at a greater skinfold depth than the M probe, the relatively newer XL probe now overcomes some of the difficulties with obtaining successful vibration-controlled transient elastography readings in obese patients. However, liver stiffness measurement with the XL probe is around 2 kPa lower than with the M probe, and validated thresholds for fibrosis stage in chronic hepatitis C (or other chronic liver disease) have not yet been established. Transient elastography reliability decreases with a body mass index greater than 30, and significant steatosis (for example in chronic hepatitis C genotype 3 or concurrent non-alcoholic fatty liver disease) may underestimate fibrosis stage, with failure rates of up to 25 percent even with the XL probe.
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Apart from obesity and operator inexperience, other important liver stiffness measurement confounders that are independent of fibrosis include inflammation, cholestasis, and food intake.4 Based on liver stiffness measurements, elevation in alanine aminotransferase greater than 100 IU/L may place chronic HCV patients with F0-2 fibrosis into the cirrhotic range. Fortunately, chronic HCV is not associated with significant hepatic transaminase flares, which can lead to three-fold elevations in liver stiffness measurement as seen in chronic hepatitis B (HBV) infection. Also, transient elastography assessments are scheduled throughout
the entire day, so a strict requirement for a two-to-three hour fasting period is often not feasible and is overlooked for point-of-care testing, particularly if there is no requirement for prior authorization and a return visit. A 600 Kcal meal will increase liver stiffness measurement for one-to-two hours, and could easily place a patient with moderate-advanced disease into the cirrhotic range.4 Alcohol excess, or other co-morbid conditions that lead to hepatic congestion (right heart failure) or cholestasis, will also significantly elevate liver stiffness measurement. Thus, transient elastography should be performed by an experienced operator in fasting patients (for at least two to three hours), taking into account alanine aminotransferase levels, body mass index, alcohol intake and other co-morbid states.
Liver stiffness measurement thresholds have been validated for chronic HCV but vary in HIV-HCV co-infection or other chronic liver diseases. Vibration-controlled transient elastography is useful for the exclusion of cirrhosis, but has similar accuracy for significant fibrosis (greater than or equal to F2) as serum fibrosis markers that are readily available, and also provide an alternative for discordant findings (between transient elastography and other clinical/radiological/ biochemical assessments). Transient elastography and other noninvasive tests cannot differentiate between adjacent stages of fibrosis. Repeating alanine aminotransferase at relatively short intervals (three-to-six months) as is often done in clinical practice, will not provide any meaningful assessment in terms of changes in disease severity and is more likely to be influenced by observer error. It is important to remember that liver stiffness measurement readings will likely be lower in chronic HCV patients following sustained virologic response. This is due to reduced necroinflammation and normalization of liver transaminases, and not regression of fibrosis. Of clinical relevance, patients with persistent chronic HCV cirrhosis on biopsy following sustained virologic response may have early reductions in liver stiffness measurement and could be placed in lower fibrosis stage categories that could be falsely reassuring to both the clinician and patient. Actual changes in liver stiffness measurement that reflect fibrosis remodeling may take two-to-three years following sustained virologic response.5
The ease of use and familiarity with transient elastography often results in application to disease states without established thresholds. I have seen requests for transient elastography by experienced clinicians for fibrosis assessment in patients with potential methotrexate-induced liver injury or autoimmune disease, with non-validated chronic HCV thresholds subsequently used to report an estimated fibrosis stage. Vibration-controlled transient elastography may be useful for predicting complications from portal hypertension. However, liver stiffness measurement readings for hepatic vein portal pressure gradient greater than or equal to 10 to 12 are influenced by significant changes in hemodynamics rather than fibrosis, and at this time, transient elastography cannot be used to follow changes in hepatic vein portal pressure gradient in decompensated disease, or replace GI endoscopy for varices surveillance.6
Transient elastography (along with other imaging methods and blood tests) certainly represents a significant advance in our field. With appropriate use, and cautious interpretation in the context of quality metrics and understanding of device limitations, transient elastography now provides complementary and clinically relevant information, to the health-care provider for the assessment of liver-disease severity.
Dr. Patel has served as a consultant, advisor or has conducted data monitoring for Gilead, Nitto-Denko, Bristol-Myers Squibb, Benitec and Merck.
1. Patel K, Bedossa P, Castera L. Diagnosis of liver fibrosis: present and future. Semin Liver Dis 2015;35:166-83.
3. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015;63:237-64.
5. Tapper EB, Castera L, Afdhal NH. FibroScan (Vibration-Controlled Transient Elastography): Where Does It Stand in the United States Practice. Clin Gastroenterol Hepatol 2015;13:27-36.
6. Arena U, Lupsor Platon M, Stasi C,Moscarella S, Assarat A, Bedogni G, Piazzolla V, Badea R, Laffi G, Marra F, Mangia A, Pinzani M. Liver stiffness is influenced by a standardized meal in patients with chronic hepatitis C virus at different stages of fibrotic evolution. Hepatology 2013;58:65-72.
7. Pinzani M. Liver Fibrosis in the Post-HCV Era. Semin Liver Dis 2015;35:157-65.