Sonoelastography: Ultrasound Method to Measure Liver Fibrosis
Sonoelastography: Ultrasound Method to Measure Liver Fibrosis
HYPOTHESIS: The investigators hypothesize that sonoelastography (SE) will provide accurate
 quantitative measurements that can be used to stage liver fibrosis in patients with chronic
 liver disease.

 1. To measure liver stiffness with sonoelastography in adults with suspect diffuse liver
 disease who will undergo non-focal liver biopsy as part of their routine clinical care

 2. To assess the sensitivity and specificity of sonoelastography for the detection and
 staging of liver fibrosis

 3. To evaluate the effect of steatosis and inflammation on the estimation of liver fibrosis
 using sonoelastography
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

 1. To evaluate liver stiffness with the diagnostic imaging method of sonoelastography among
 adults with suspect liver diseases.

 2. To obtain estimates of the sensitivity and specificity of sonoelastography for the
 detection and staging of liver fibrosis.

 STUDY PROCEDURES Study Visit 1: (SE or sonoelastography )

 -  Sonoelastography will be performed prior to standard pre-biopsy ultrasound imaging using
 a FDA-approved ultrasound unit. This unit will use ultrasound energy within the limits
 set by the FDA for diagnostic ultrasound to create a shear wave front that is
 progressively distorted as it traverses the tissue. Ultrafast ultrasound imaging will
 then be used to detect the speed of propagation of the shear wave front.

 -  The unit will emit no ionizing radiation and will perform ultrasound acquisition within
 the acoustic power and intensity limits established by the FDA for diagnostic
 sonography. At these energy levels there are no known bioeffects of ultrasound.
 Sonoelastography measurements will require approximately 15 minutes, and will be
 painless.

 -  The unit is a cart-based ultrasound system used to perform non-invasive diagnostic
 ultrasound studies. The system functions in a manner identical to all diagnostic
 ultrasound systems and transducers for the conventional modes: B-mode, Harmonic imaging,
 Spatial Compounding imaging and Power Doppler. Additionally, the system uses a new
 imaging mode based on shear wave elastography to map tissue stiffness. The elastography
 mode produces color-coded images of different tissues based on their elasticity. The
 color scale represents a quantitative assessment of tissue stiffness, thereby allowing
 elasticity of tissue to be quantified in units of kilopascals (kPa).

 -  At the conclusion of Study Visit 1, the patient will return to usual care.

 Tests and Parameters:

 Sonoelastography parameters:

 Mean liver stiffness (elastogram) in kilopascal (kPa). SE normal values approximately 5.5 kPa
 (Normal liver stiffness ranges between 3.3-7.8 kPa) Significant Fibrosis (F3): = or > 7.6
 kPa, Cirrhosis (F4): = or > 9.0- 26 kPa Data Collection

 Data to be collected includes:

 -  Gender, ethnicity, age, body mass index (BMI), history of previous and current
 medication use, detail history of alcohol intake, comorbidities, signs and symptoms.

 -  Biochemical liver tests that are typically performed as part of routine clinical care
 (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase
 (APH), gamma-glutamyl transferase (GGT), tuberculosis (TB), indirect bilirubin (IB),
 direct bilirubin (DB), albumin, total proteins, prothrombin time (PT)).

 Other laboratory data typically performed as part of routine clinical care: red blood cells
 (RBC), white blood cells (WBC), platelets, glucose, creatinine, lipid profile.

 Any laboratory study for the diagnosis of the suspected diffuse liver disease: Viral
 serology, including hepatitis C virus (HCV), hepatitis B virus (HBV), ferritin,
 ceruloplasmin, antimitochondrial antibody (AMA), antinuclear antibody (ANA),
 alphafetoprotein: Sonoelastography report, and/or histological examination by a
 sub-specialist pathologist:

 -  SonoElastography

 -  Normal liver stiffness ranges between 3.3-7.8 kPa, Significant Fibrosis (F3): 7.6
 kPa

 -  Cirrhosis (F4): 9.0- 26 kPa

 -  Histology (Meta-analysis of Histological Data in Viral Hepatitis [METAVIR]):

 -  F0- No fibrosis, F1- Portal fibrosis without septa, F2- Portal fibrosis with rare
 septa, F3- Numerous septa without cirrhosis, F4 - Cirrhosis STATISTICAL ANALYSIS
 Descriptive statistics will be shown as mean ± standard deviation or percentages as
 appropriate. The patients will be divided according to fibrosis stage. The groups'
 binary diagnostic by different diagnostic methods will be compared with the gold
 standard by McNemar's Test. We will use contingency tables to analyze the
 correlation between sonoelastographic measurements. Factors independently
 correlated with liver stiffness will be assessed by multiple regression analysis.
 The diagnostic performance of fibrosis and/or liver stiffness will be determined in
 terms of sensitivity, specificity, positive and negative predictive values,
 diagnostic accuracy and area under receiver operating characteristics (ROC) curves.
 This is a pilot study and the investigators are planning to enroll 100 participants
 to include in this study. With 100 patients included in this study the
 investigators can have a > 80% power to detect a significant diagnostic power by
 SonoElastography with a true AUC between of 0.85 as opposed to the null with an
 area under the curve (AUC) of 0.62 or lower using a two-sided test with 5% type I
 error. In addition, multivariate linear and logistic regression models will be used
 to evaluate the diagnostic power of independent factors taking into account
 possible confounders by patient demographic and clinical characteristics. The
 primary outcome of interest will be fibrosis.

 RISKS AND DISCOMFORTS Ultrasound Elastography: Ultrasound elastography requires the
 administration of ultrasound energy at levels similar to those used in diagnostic
 ultrasonography. There are no known bioeffects of ultrasound at these energies.

 Pregnant women are excluded from this study. There are no known risks of sonoelastography to
 an embryo or fetus (a developing baby still in the womb). There may be risks to an embryo or
 fetus that are currently unknown.

 POTENTIAL BENEFITS Although knowledge about liver diseases and fibrosis has increased
 dramatically over the last few years, much remains to be learned. The imaging strategy that
 will be evaluated, ultrasound sonoelastography, has the potential to reduce the number of
 liver biopsies performed for the diagnosis and monitoring of hepatic fibrosis. This study is
 expected to provide a basis for future investigation into non-invasive imaging markers of
 hepatic fibrosis. Any data obtained for the purposes of this study will be available to the
 participant's primary physicians.
Inclusion Criteria:

 -  Adult patients (age 18 or older)

 -  Men or women

 -  Suspected diffuse liver disease

 -  Consent to participate in the study

 Exclusion Criteria:

 -  Pregnancy

 -  Acute illness/cognitive impairment resulting in inability to cooperate with
 ultrasound.

 -  Patients that do not consent to ultrasound or sonoelastography.