Challenges in Staging Liver Fibrosis
By TIMOTHY J. HALL, PhD
Chronic fibrosis can disrupt liver function and progress to cirrhosis, the final phase of chronic liver disease—one of the major causes of death in the U.S. Staging fibrosis is a key to determining liver health. Although core biopsy is the current clinical standard for staging fibrosis, its accuracy is limited by the heterogeneity of the disease and the small sample size. Further, liver biopsy is painful and is associated with several potential complications.
Noninvasive quantitative measures of liver stiffness have been proposed as surrogate measures of liver fibrosis since the excess collagen increases the elastic modulus of tissue. Typical sound waves (including ultrasound) are "longitudinal" or "compressional", meaning wave propagation moves in the direction of the disturbance of the wave action. A "shear" or "transverse" wave, commonly associated with earthquakes, can be created in tissue using a relatively long duration and relatively high-intensity compressional wave to push the tissue—in a very localized area—a few microns. That action causes movement in the tissue next to it, creating a wave traveling perpendicular to the direction of the compressional wave propagation. In simple media (homogeneous, isotropic, large compared to the wavelength) the speed of shear waves (cs) is directly related to the shear modulus (µ) of the medium (µ = ρ cs2 where ρ is mass density). New ultrasound techniques, found on some of the most advanced imaging systems, can create and track shear waves to estimate their speed and thus, noninvasively provide quantitative estimates of liver stiffness and liver fibrosis.
Studies found in the MR imaging and ultrasound literature have compared shear wave speed (SWS) and fibrosis stage from core biopsy. The research demonstrated excellent correlation, especially considering the uncertainties in the staging. Using the nonalcoholic steatohepatitis Clinical Research Network scoring system to grade the biopsy specimens, SWS can differentiate bridging fibrosis (stage 3) and cirrhosis (stage 4) from normal tissue and the more mild stages of fibrosis (stages 0-2; see figure 1). Unfortunately, the threshold SWS for classifying fibrosis varies among different imaging systems. The QIBA Ultrasound Shear Wave Speed Technical Committee is challenged to understand the sources of bias and variance in these measurements and to develop methods for direct comparison of results obtained with different imaging systems and system configurations.
Ultrasound methods for generating shear waves in tissues create individual pulse packets of shear waves that propagate only a few millimeters before the energy is absorbed by the tissue. The SWS of these packets (the "group velocity" of the shear wave) is the quantity currently estimated by ultrasound imaging systems. A wave packet is the superposition of waves from a range of frequencies (each having their own "phase velocity"). One difficulty in direct comparison of shear wave speeds (group velocities) among different imaging systems and configurations is that different system configurations produce shear waves with different frequency content (superposition of different phase velocities over different frequency ranges).
One approach the Committee is considering is the direct comparison of a single-phase velocity that is common among each of the different systems and system configurations for the specific task of staging liver fibrosis. As simple as it might seem, it is essential to get the details right for direct comparisons. An alternative, model-based approach might be to use a constitutive model (relating stresses to strains in fibrotic liver tissue) to map the group velocity measured with one system to the group velocity measured with another system.
Although the QIBA Ultrasound Sheer Wave Speed Technical Committee is very new, and the task is quite challenging, this is a broadly representative, outstanding group of scientists, clinicians and industry representatives who are committed to the goal and actively involved in defining and addressing this important clinical need. Application of the approach to many other SWS biomarkers could follow rapidly.
Figure 1. A box plot of ultrasound-measured shear wave speed for various stages of liver fibrosis. The numbers of subjects in each group are shown in parentheses. (Data replotted from Palmeri, et al, J Hepatology 55(3): 666-672, 2011, with permission from the lead author).
Timothy J Hall, PhD, is a professor in the Medical Physics Department at the University of Wisconsin, Madison. He is co-chair of the QIBA Ultrasound Shear Wave Speed Technical Committee and co-chair of the Phantoms Subcommittee. His research group has been developing, implementing and testing quantitative ultrasound techniques for 25 years.
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