What Is Known/What Is New
What Is Known
- Transient elastography is a promising noninvasive technique to assess fibrosis in both adults and children.
- Several modalities are utilized to perform transient elastography including ultrasound, magnetic resonance imaging and vibration controlled transient elastography.
What Is New
- Transient elastography measurements have been studied and found to be feasible in most children.
- Transient elastography measurements in different pediatric liver diseases correlate with liver fibrosis on biopsy in the specific diseases.
- Limitations exist in the interpretation of transient elastography measurements as they can be affected by the presence of severe inflammation, hepatic congestion, obesity, as well as nonfasting state.
Progression of fibrosis in children with chronic liver disease leads to the development of cirrhosis and complications of portal hypertension. Although liver biopsy is considered the gold standard for monitoring the progression of fibrosis, it is limited by sampling error, risk of small biopsy size, cost, and subjective interpretation, and by risks of complications from an invasive procedure (1). Noninvasive measures of fibrosis including imaging techniques and biomarker measurements have been widely studied to identify surrogate measures of fibrosis and disease progression.
Transient elastography has shown promise in both adults and children with chronic liver disease as a noninvasive technique to assess fibrosis. The aim of this review is to provide an overview of transient elastography technology and highlight the recent data on its use in assessing fibrosis in children with chronic liver disease.
TRANSIENT ELASTOGRAPHY TECHNIQUES AND TECHNOLOGY
Liver elastography encompasses a variety of techniques ranging from vibration-controlled transient elastography (VCTE), magnetic resonance (MR) elastography to acoustic radiation force-based elastography (1,2). The underlying principle of these modalities is the use of shear wave elastography to measure tissue stiffness. A probe generates a shear wave that propagates through the liver and the velocity of this propagation is recorded by a receiver probe. This velocity is then commonly converted to a measurement of liver stiffness, which is measured in kilopascals (kPa). This measurement correlates with liver stiffness, and subsequently, the degree of fibrosis (1–3). The differentiating factor between these modalities is the type of shear wave generated by the probe (Table 1) (3).
TABLE 1 -
Different modalities for elastography in children
||Type of waves
||Pros and cons
|Acoustic Radiation Force Index (ARFI)
||Standard ultrasound probes
||Real-time images of the liver allowing avoidance of masses and large vesselsClassified as 2-dimensional shear-wave elastography, allowing for larger field of view to be included
||Additional imaging of liver possible at the same timeConfounded by hepatic congestion, obesity, nonfasting status, presence of hepatic inflammation
|Magnetic resonance elastography
||Passive driver placed on patient
||MR scanner acts as probeFull cross-sectional imaging of the liver performed simultaneously
||Additional cross-sectional imaging of the liverHigher success rates in patients with severe obesityLimited availability across centersSignificant costSedation required for younger pediatric patients
|Vibration-controlled transient elastography (VCTE)that is, FibroScan (Echosens, Paris, France)
||Standard ultrasound probes
||Classified as 1-dimensional shear-wave elastography without use of direct image guidance and single field of view used
||FibroScan device (Echosens, Paris, France) easily available to be performed in outpatient, clinic settingOperator experience may influence measurementsConfounded by hepatic congestion, obesity, nonfasting status, presence of hepatic inflammation
VCTE is the most commonly used modality worldwide and the FibroScan technology (Echosens, Paris, France) has been the most widely used form of VCTE within the pediatric clinical and research setting (4). VCTE relies on vibrations of a mild amplitude and low frequency (50 Hz) generated from a probe as inducers of a shear wave through the liver. The velocity of this shear wave is directly related to the stiffness: the stiffer the tissue, the higher the velocity (2,3). VCTE is considered a 1-dimensional shear wave elastography as direct image guidance is not used, and measures tissue stiffness over an area approximately 100 times the size of a standard liver biopsy specimen (2,3,5). VCTE can easily be performed at the bedside in the outpatient clinic setting, takes less than 5 minutes to perform, and is painless. The user generates at least 10 validated measurements with the corresponding median value reported as the liver stiffness in kilopascals (Fig. 1). The Controlled Attenuation Parameter (CAP) is useful in quantifying hepatic steatosis by calculating the energy loss of the shear wave as it passes through the liver tissue. A recent meta-analysis in adults assessing use of CAP to assess degree of hepatic steatosis found that a cut-off value of 268 dB/m (95% confidence interval [CI] 257–284 dB/m) was optimal at predicting steatosis above grade 1 (6). The use of CAP in children will be discussed in more detail later in this article.
Several potential confounders need to be considered whenever interpreting liver stiffness results from VCTE. Any physiologic or pathologic process that may increase the depth of the liver from the skin, such as ascites or significant obesity may affect these measurements. Studies in adults have shown that the rates of VCTE failure and unreliable examinations were much higher in patients with BMI >30 kg/m2(7). Factors that can alter the viscoelastic properties of hepatic tissue, such as inflammation, vascular congestion, for example, Fontan-associated liver disease, or hepatic blood flow alterations caused by meal ingestion, may lead to falsely elevated liver stiffness measurements (4,8). Other considerations specific to children include age, ability to lay still and cooperate, and probe size. Success rate is lower in children less than 24 months of age and using a small probe in a larger child may lead to an erroneously high liver stiffness measurement (8).
Ina addition to VCTE, additional modalities exist for the measurement of liver stiffness with the main differentiating factor being the type of shear wave generated, as presented in Table 1. In acoustic radiation force-based elastography, acoustic waves are generated by standard ultrasound probes to generate the shear waves for tissue displacement and stiffness measurements (3). This type of elastography relies on real-time imaging so that any masses and large vessels can be avoided. It is categorized into point-shear wave elastography (pSWE), where only a single point within the liver is chosen for the measurement, or 2D-shear wave elastography (2D-SWE), where multiple pulses are used to generate shear waves in a larger field of view (5). MR elastography also relies on the generation of acoustic waves from a passive driver placed on the patient but rather the MR imaging (MRI) scanner acts as the probe interpreting the shear waves generated (9). It is important as clinicians to understand the differences between the various technologies that exist to measure liver stiffness, as based on the vendor and probe used, cut-off values may differ across vendors (5). The remainder of this manuscript will focus on the use of VCTE in children.
APPLICATION OF VIBRATION-CONTROLLED TRANSIENT ELASTOGRAPHY IN CHILDREN
The primary goal of using VCTE is as a noninvasive marker in the assessment of liver fibrosis, determining progression of fibrosis, and avoiding the need for invasive testing, such as liver biopsy. Studies in children have been performed to identify liver stiffness measurement (LSM) cut-off values that correlate with degree of fibrosis on liver biopsy (Fig. 1). Different cut-off values may exist depending on the modality of shear wave elastography used and may not be interchangeable, as described above (3,10). A recent study comparing different modalities in assessment of normal liver stiffness values in children found that valid measurements could be obtained in all modalities, and that LSM values increased as a child's age increased and higher LSM values are seen in boys as compared with girls (11). A recent prospective study found similar findings with significantly higher median LSM values in adolescent boys as compared with adolescent girls (12). LSM values in healthy children in these studies were similar to previously published norms of liver stiffness with mean LSM 4.6 kPa by VCTE (8,11,13,14).
Assessment of cut-off LSM values that predict degree of fibrosis on liver biopsy has shown varied results for a variety of liver diseases in children (Table 2). A report from China demonstrated significantly different mean LSM in children with biliary atresia (BA) who had liver fibrosis scale METAVIR stage 2 fibrosis on liver biopsy compared with METAVIR stage 4 fibrosis, with a sensitivity of 86% and specificity of 92% at predicting the presence of stage F4 fibrosis on liver biopsy (15). Additionally, studies in children with chronic liver disease have also shown LSM useful in distinguishing the presence of significant fibrosis (METAVIR ≥F2) (12), with meta-analysis showing the diagnostic accuracy of shear-wave elastography for significant liver fibrosis (≥ F2) to be 81% and specificity 91% (10). These promising results may suggest a role for routine use and serial monitoring of progression of liver disease using VCTE in children with chronic liver disease.
TABLE 2 -
Cut-off values for liver stiffness using vibration-controlled transient elastography
||Median liver stiffness measurement using VCTE (FibroScan technology)
||Cut-off value > 15.5 kPa distinguishes METAVIR F4 fibrosis (15)Cut-off value >12.7 kPa predicts development of esophageal and gastric varices (18)
|Any chronic liver disease
||Cut-off value >10.6 kPa distinguishes METAVIR ≥F2 fibrosis (12)
|Nonalcoholic fatty liver disease
||Cut-off value >9 kPa distinguishes presence of advanced fibrosis (24)Cut-off value of CAP parameter >225 dB/m distinguishes presence of steatosis (23)
||Cut-off value >9.7 kPa distinguishes presence of portal hypertension (16)
|Liver transplant graft
||Cut-off value >5.6 kPa distinguishes METAVIR ≥F2 graft fibrosis (22)
VCTE = vibration-controlled transient elastography.
In addition to predicting degree of liver fibrosis, VCTE has been studied to predict the presence of portal hypertension in children. A recent meta-analysis found sensitivity of 90% and specificity of 79% of using shear-wave elastography at predicting the presence of portal hypertension (16). A large study assessing LSM in patients with BA, Alagille syndrome, and alpha 1 antitrypsin deficiency demonstrated a correlation between higher LSM and clinically evident portal hypertension (17) and has even been shown to predict the development of esophageal and gastric varices in children with biliary atresia (18).
As heterogeneity exists in the cause of chronic liver disease, it is important to address the use of VCTE to specific patient populations. A recent retrospective study assessed the change in liver stiffness measurement annually in patients with cystic fibrosis (CF) and patients who developed CF-related liver disease (CFLD). Patients who developed CFLD had a more rapid increase in LSM values per year than children who did not develop CFLD (19). A recent study aimed at identifying Fontan-associated liver disease (FALD) found that LSMs were significantly higher in patients who had liver ultrasound evidence of cirrhosis, and increased LSM correlated significantly with Fontan duration (20).
VCTE has also been applied in children after liver transplantation to assess degree of allograft fibrosis. Liver stiffness measurements were noted to be significantly higher in children with significant fibrosis on allograft biopsy (METAVIR stage ≥F2) compared with those without significant fibrosis (METAVIR F0/F1) with a sensitivity of 75% and specificity of 95.8% (21,22).
Lastly, there has been growing interest in using VCTE as a modality to track disease progression in nonalcoholic fatty liver disease in children. Application of the CAP parameter to assess degree of steatosis has been studied in children and has been shown to predict the presence of steatosis with a sensitivity of 87% and specificity of 83% (23). Additionally, a study correlating VCTE with degree of fibrosis on liver biopsy in children with steatohepatitis showed values of at least 9 kPa were associated with the presence of advanced fibrosis (24).
As the use of VCTE expands in the clinical and research settings, direct application to patient care should be a priority as research expands and VCTE technology is adopted in clinical care. LSM measurements may be integrated into decision-making of clinicians using screening endoscopy for varices in patients with clinically significant or clinically evident portal hypertension. Additionally, as more studies are published on the use of VCTE, incorporation of LSM as a possible marker of disease progression may be possible. Lastly, as the field of pediatric liver transplantation continues to evolve and more data on the use of VCTE in this population is published, potential integration of LSM into long-term surveillance assessment of allograft fibrosis that may provide a novel use of this technology.
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