Ultrasound elastography in children — nice to have for scientific studies or arrived in clinical routine?

Ultrasound is the central imaging method in pediatric diagnostics caused by the neglectable risk profile and high availability. In addition to fundamental B-mode sonography, Doppler modalities and contrast-enhanced ultrasound elastography (USE) were introduced more than 20 years ago into the clinical routine in adults increasing the diagnostic power of ultrasound examinations.

In medicine, palpation is a standard diagnostic tool in clinical examination and has always been used to differentiate benign and malignant lesions using the criteria of size, displaceability, compressibility, hardness, and consistency. Unfortunately, only superficial structures are accessible to palpation. Furthermore, palpation is a subjective method and strongly dependent on the experience of the physician. These limitations can be overcome with elastography, a procedure developed for both magnetic resonance (MR) and ultrasound. While MR elastography has so far not been able to establish in clinical routine due to considerable expenditure, USE plays an increasing role.

Elastography is used to measure noninvasively the internal tissue deformation that results after application of a force. According to the English ophthalmologist and physicist Thomas Young (1773–1829), elasticity is described using the modulus elasticity E, which is calculated from the ratio of tension to stretching of the tissue. The extent of relative changes in length when an external or internal force is applied depends on the elastic properties. Young’s modulus for diamond as the hardest material is 1220 GPa (Gigapascal), healthy soft tissue is between 0.5 and 70 kPa (Kilopascal), and healthy liver tissue is between 0.4 and 6 kPa [54].

Focal and diffuse findings of tissues could be described in more detail in terms of their elasticity. Starting with the evaluation of liver diseases in adults at the end of the 1990s, the horizon of elastography has subsequently expanded significantly. It was used to asses classic malignancies (e.g., breast cancer, prostate cancer) but also to evaluate superficial organs such as the thyroid gland and their focal lesions. Guidelines about the use of elastography in adults were published and updated by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and the World Federation for Ultrasound in Medicine and Biology (WFUMB) in adults for hepatic and non-hepatic applications [13, 22, 48]. Up to now, there are only few reports about features of elastography and techniques in children ([14], Mentzel 2020 [42]).

The method of static elastography is based on the work of Ophir et al. who published elastograms based on the correlation analysis of tissue displacement under pressure [46]. At the beginning of the new century, dynamic elastography was developed superimposing elasticity values in color on the fundamental B-mode image in real time (real-time elastography, RTE). The strain image results from the different shifts of the echo frequency pattern under mechanical pressure (external compression, internal pulsation, breathing movement) on the analyzed tissue, with elastic tissues approaching the frequency peaks, while with stiff tissues, they remain at a constant distance. Rigid structures are usually shown in blue, intermediate deformable tissue parts are shown in yellow-green, and easily deformable tissue parts are shown in orange-red. Strain elastography provides a color-coded, qualitative result. The strain ratio can be used to estimate at least a ratio of the stiffness of the region of interest (ROI) to the surrounding area. Dynamic USE using shear waves is based on a focused impulse that propagates as a shock wave with a propagation speed of 1540 m/s into the tissue and leads to a compression (virtual touch). Compression is followed by the release of shear waves during the relaxation process. Shear waves propagate according to the rigidity of the environment. The speed of the shear waves (around 1–10 m/s) can be evaluated by a second ultrasonic pulse (acoustic radiation force impulse, ARFI) [21, 44]. Transient elastography (TE) with FibroScan© (Echosens, Paris, France) developed for liver elastography uses both ultrasound around 5 MHz and shear waves with 50 Hz generated by a defined external impulse vibrations. The result is given in kPa as an average of ten subsequent measurements [47]. Disadvantages of this well-standardized procedure are the lack of image control where the pulse is placed and the limitation in obese patients as well as in cases of ascites. ARFI is now widespread and available on most modern ultrasound devices with conventional transducers. A distinction has to be made between ARFI imaging as a qualitative method with representation of tissue deformation as a two-dimensional image and ARFI quantification (e.g., virtual touch quantification, VTQ, Siemens; Elast PQ, Philips) as quantitative tool (point shear wave elastography, pSWE). The measurement area is defined and placed as region of interest by means of B-mode imaging. In the past, ARFI has been expanded to include shear wave elastography (2D-SWE), in which the impulses are applied to a quantification box (Q-Box) at different tissue depths (e.g., supersonic shear imaging, SSI, Aix-en-Provence, France; virtual touch imaging quantification, VTIQ, Siemens, Germany; SWE, Philips, Netherlands; 2D-SWE, GE, USA; acoustic structure quantification, ASQ, Canon, Japan). The size of the evaluated region can be varied in real time, and the shear wave velocity (m/s) or the stiffness (kPa) can be specified [51] (Fig. 1).

The various techniques of USE can be compared among each other only with great caution. Measurements with different devices from various manufacturers, even data collected with different transducers on the same device, can hardly be related to one another. This must be taken into account for any follow-up checks at time intervals. Standardization of one’s own approach is required.

The liver is generally the organ most frequently evaluated by elastography. In addition to some reference value studies in children [41, 43], there are numerous clinical studies published on detecting and grading liver fibrosis as well as on diagnosis and treatment follow-up of biliary atresia in childhood ([16, 32]; Kim JR et al. [39];). Liver stiffness data can be expressed in kPa using TE or in m/s using pSWE or 2D-SWE. The software in modern ultrasound devices allows for conversion of m/s to Young’s modulus kPa for SWE. To assess diffuse liver changes, the right lobe of the liver is usually examined in segment 7. An intercostal access in a supine position with the right arm in extension gives more reproducible data than the evaluation of the left liver lobe [14]. Breath-hold minimizes measurement variability but can be difficult in children below the age of 5 years. Fast 2D-SWE evaluation with free-breathing gives results similar to breath-holding [37]. The liver should not move during the measurement. Region of interest is placed perpendicular to 2 cm subcapsular in the liver. It has proven useful to acquire 10 measurements and to use the median for further assessment [45]. In addition to age and gender, factors influencing liver stiffness are the positioning of the transducer and the region of interest as well as the blood flow to the liver, which depends on the time of last meal. The best reliability in the assessment of the liver stiffness is in examinations using 2D-SWE compared to pSWE and TE [38, 43]. There are promising USE studies for the evaluation of cystic fibrosis-related liver diseases (CFLD) [25]. A cutoff value of 1.27 m/s for CFLD was published achieving a specificity of 97% [9, 10]. For non-alcohol-related steatohepatitis (NASH), the combination of SWE and laboratory parameters has proven to be a biomarker of the severity of this entity [57]. In biliary atresia cases of post-Kasai liver fibrosis, ARFI can be used to assess liver fibrosis and to guide further treatment decisions like the urgency of liver transplantation [15, 29]. Further USE applications include the evaluation of liver pathology in alpha-1-antitrypsin deficiency, autoimmune hepatitis, veno-occlusive disease, hemochromatosis, Wilson’s disease, autosomal recessive polycystic kidney disease, and monitoring after liver transplantation [14, 28] (Fig. 2). USE plays a fixed role in the assessment of relevant liver pathologies and can be classified as a diagnostic component after clinical examination and standard liver laboratory prior to invasive liver biopsy [20, 24]. When evaluating liver elastography values, it should be borne in mind that there is a direct correlation with right-sided cardiac function. Every pathology of the right heart leads to pressure changes in the upstream vascular system, to the hepatic veins via the inferior vena cava. Due to the relatively coarse liver capsule, the changes in vascular pressure also lead to changes in rigidity. Each congestion ultimately leads to increased stiffness in the liver tissue. In children with congenital heart defects, liver stiffness can be used as a prognostic marker for cardiac events [23].

While USE of the liver has meanwhile arrived in the clinical routine with children and adolescents, so far, all other applications are only poorly established.

Limitations lie in the inadequate standardization of the method. There is variability of measurement results using different devices and probes. In the liver, it could be shown that the results of USE are depending on a large number of variables. Compliance of the patient is necessary in most techniques of ultrasound elastography. The approval of ultrasound elastography is limited for use in abdominal, breast, thyroid, small parts, and musculoskeletal examinations. Shear wave elastography is approved by the Food and Drug Administration (FDA) in children and in adults.

The safety of ultrasound is monitored using thermal index (TI) associated with heating effects and mechanical index (MI) associated with cavitation effects. Both indices should be kept as low as possible. Potential risks arising from the energetic ultrasonic push pulse in elastography using acoustic displacement techniques (ARFI, SWE) must be considered [50]. The maximum temperature is at the focus of the evaluated region. The heating increases with the number of pulse sequences and scanning duration. Using a very strong ARFI, a temperature rise of 1.2 °C was estimated in a worst-case scenario (Fahey et al. 2015 [21]). But, in a 2D SWE study on mice, no histologically negative effects were found by SWE [40]. However, some temporary limited effects were observed if the scanning procedure lasted more than 30 min. As mentioned by the EFSUMB, the as low as reasonably achievable (ALARA) principle should be applied when setting the output for ARFI, and scanning time should be kept short [18]. Especially in case of vulnerable tissue (e.g., ovarian or testicular torsion, ischemic brain tissue), caution is necessary.

Ultrasound elastography which has been known for around 30 years was adopted into clinical routine in adulthood. The existing guidelines on adults may not be immediately transferrable to children [14]. Most of the experience with the use of various ultrasonic elastography methods comes from liver examinations — here, due to existing reference and cutoff value studies, elastography has now in many places become part of the routine in children and adolescents. But, there is still ample research potential for elastography in other organ systems.