Evaluate the Utility of Shear Wave Sonoelastography as a Tool to Measure Liver Fibrosis Grade

BACKGROUND Chronic liver disease is an important cause of morbidity and mortality in the United States. A retrospective cohort study identified 2,353 patients with newly diagnosed chronic liver disease (63.9 cases/100,000 population). Extrapolating this incidence rate there will be approximately 150,000 patients with chronic liver disease diagnosed in gastroenterology clinics each year. Almost 20%, or an estimated 30,000 patients per year, had established cirrhosis at the time of presentation to the gastroenterologist.

Cirrhosis remains a major public health problem and disease-related complications were associated with nearly 40,000 deaths and more than 1.4 billion dollars spent on medical services in the United States. There is a great need to develop and identify methods of risk stratification and prognostication for patients with chronic liver disease. Hepatic fibrosis is the final common pathway for many different liver insults and is now known to be a dynamic process that is at least partially reversible. The diagnosis and quantification of fibrosis relies on liver biopsy, and liver biopsy is currently the gold standard for detecting and staging hepatic fibrosis. However, liver biopsy is an invasive procedure with significant risks, including hemorrhage, infection and visceral perforation. In addition, liver biopsy is a poor gold standard, because it is limited by interobserver variability in interpretation and sampling errors in 25-45% of cases.

A number of indirect markers and indices of liver fibrosis have been used in clinical practice. Noninvasive tests can be distinguished by direct vs. indirect measures of fibrosis and also classified by the modality of the test as serum vs. imaging. Biomarkers of the structural elements of fibrogenesis and the key inflammatory mediators involved in the genesis or degradation of scar tissue are often referred to as direct components. Indirect markers can reflect the accompanying alterations in hepatic function.

Fibrotic livers demonstrate increased stiffness. This property can be exploited and measured using a newly developed ultrasound technology named Ultrasound Elastography (Transient Elastography (TE) or sonoelastography (SE). SE is performed by insonating the patient with a low energy, low amplitude, and low frequency shear wave created by focused ultrasound or by a vibrating probe on the skin. The small tissue movements produced by the propagated wave are then measured with ultrasound. The propagated wave travels faster with increasing fibrosis: the stiffer the tissue, the faster the shear wave propagates. A pulse-echo ultrasound acquisition allows measurement of the wave velocity and the results are presented as kilopascals (kPa). Tissue elasticity is calculated as the median of 10 measurements and ranges from 2.5 to 75 kPa with normal values around 5.5 kPa (Normal liver stiffness ranges between 3.3-7.8 kPa). Hepatic stiffness can be measured within a cylinder of tissue 1 cm wide and 4 cm in length producing an estimated sampling area that is 100 times greater than a biopsy. A meta-analysis assessing the capacity of transient elastography to diagnose moderate fibrosis found pooled estimates for sensitivity and specificity of 70% and 84% respectively. The mean area under the receiver operating characteristic curve (AUROC) for the diagnosis of significant fibrosis was 0.84% with an optimal cut-off of 7.6 kPa, and the diagnostic accuracy of SE for cirrhosis had an AUROC ranging from 0.90- 0.99 (mean AUROC 0.94) and cut-off from 9.0 to 26.5 kPa. The benefits of SE are that it is inexpensive, reproducible, painless, rapid (<10 min), easy to perform, and can be used for diagnosis, prognosis and monitoring disease progression. Limitations of sonoelastography are that measurements cannot be obtained in the presence of marked obesity, ascites, or unusually narrow intercostal spaces when externally applied vibrating shear wave generators are used.

SPECIFIC AIMS