Evaluation of Liver Fibrosis in Cirrhotic Patients: Comparison between Elastoso- nography and Fibroscan

To date, there are still no clear data on the validity of Shear Waves Elastography (SWE) techniques in assessing liver fibrosis. Our study aimed to compare the stiffness liver values obtained with SWE techniques with Transient Elastography (TE) and to identify the threshold values for the different degrees of fibrosis. We enrolled 11 healthy subjects and 48 patients with chronic liver disease. They all performed TE, 33 patients and healthy subjects were evaluated withPoint SWE and 15 patients with 2D-SWE. The differences between techniques and TE, evaluated with student’s t-test, were not statistically significant (p>0,05). The cut-offs of SWE technique were for F≥2 6,2 kPa; F≥3 7,65 kPa; F=4 13 kPa. SWE techniques have good potential in assessing liver fibrosis; moreover, being elastosonography quick and easy to perform, it could be integrated into the clinical practice of the ultrasound examination.


Introduction
Chronic liver diseases are an important public health problem, with an incidence in Europe of 5,82% [1]. They have multiple causes, many of which are increasing in prevalence.
The final common pathway of chronic liver disease is tissue destruction and attempted regeneration, a pathway that triggers fibrosis and eventual cirrhosis. Assessment of fibrosis is important not only for diagnosis but also for management, prognostic evaluation, and follow-up of patients with chronic liver disease.
For years, liver biopsy has been considered the standard reference in the staging of hepatic fibrosis. However, approximately 25% of patients experience pain during the invasive procedure, and 0.3%-0.6% of patients experience severe complications, such as bleeding and even death [2].
To replace liver biopsy, non-invasive approaches based on serologic methods, which however can be influenced by factors not related to hepatic function, and on imaging techniques were developed for liver fibrosis estimation.
To date, Fibroscan, introduced in 2003 as the first imaging technique that uses transient elastography (TE) able to measure the degree of hepatic fibrosis in a non-invasive way, is a reference point for hepatologists to classify patients with chronic liver disease [3].
Because hepatic fibrosis increases the stiffness of the hepatic parenchyma due to an increase in the extracellular matrix, elastosonography can be used to assess fibrosis degree.
This method allows analyzing tissue behavior when it is subjected to mechanical stress using ultrasound.
There are two basic methods of elastosonography: the strain method (SE) and the shear-waves method (SWE).
StrainElastographyevaluates the strain of a tissue induced by an external stimulus [4]. Shear-Wave based techniques, instead, measure the speed of Shear-waves in tissues. The main difference between these techniques is that the speed of the shear-waves, being linked to the stiffness, can be measured and converted into KPa, while the strain elastography provides only a relative estimate [5]. Shear-Wave based techniques include TE, point SWE, and 2D-, 3D-SWE.TE evaluates the speed of a Shear Wave generated by an automated movement of a piston.
Point SWE measures the average speed of Shear Wave propagation, generated using acoustic radiation force, from one lateral boundary of a measurable ROI to the opposite lateral boundary of the ROI; in 2D-, 3D-SWE the method described for point SWE is used to create even a quantitative image. The arrival time of the shear waves is evaluated in several lateral positions, this allows to create a large 2D-SWE ROI image, which is displayed in color or grayscale. In both techniques, ultrasound imaging is used to guide the placement of the ROI [6].
Nowadays almost all the manufacturers of ultrasounds have activated SWE techniques on their most recent machines, but the lack of sufficient data for these last machines, due to their recent introduction, as well as the considerable decrease in the number of liver biopsies in clinical practice, has raised some pertinent issues, in particular the possibility of using the stiffness values adopted for the staging of chronic hepatic diseases with TE also with other SWE techniques. The first studies have documented a good potential of the SWE techniques in the evaluation of liver fibrosis, but they warn about using the same thresholds of TE for different degrees of fibrosis because they found modestly lower values with SWE techniques compared to TE for the same degree of fibrosis.
Our study aimed to compare the stiffness values of the liver obtained with two different shear wave techniques with the corresponding values obtained by TE in the same patients and to identify the threshold values for the different degrees of fibrosis.

Patients
This is a prospective study. We enrolled 11 volunteer healthy subjects and 48 patients with chronic liver disease (patients and healthy subjects characteristics are shown in

TE and SWE elastography examination
The two procedures were performed on different days, within a maximum distance of 30 days from each other.
TE was performed on a patient lying supine with the right arm

Statistical analysis
The stiffness values were expressed in kPa in all techniques used. To perform the statistical analysis the data were expressed as mean and standard deviation (SD

Results
Thirty-three patients were evaluated with Point SWEand TE, the stiffness mean values were respectively 12,74 kPa ± 9,71 SD and 12,78 kPa ± 15,43 SD ( Figure 1). These parameters were evaluated through a Student's t distribution with 32 degrees of freedom. The difference between the two groups was not statistically significant (p>0,05). Fifteen patients were instead evaluated with 2D-SWE and TE, the stiffness means values were respectively 10,77 kPa ± 8,16 SD and 10,88 kPa ± 5,04 SD ( Figure   2) and also in this case t-test showed no statistically significant difference between the two groups (p>0,05).
We also calculated in SWE techniques the stiffness mean value by eliminating the measurements performed on left hepatic lobe: for Point, SWEit was 12,40 kPa ± 9,54 SD and for 2D-SWEwas 10,49 ± 7,44. Also in these cases, the differences with TE were not statistically significant (p>0,05). The stiffness mean values of 11 healthy subjects, evaluated with Point

Discussion
Fibrosis is a process characterized by an abnormal increase in the deposition of collagen and other components of the extracellular matrix. There are several systems of the staging of liver fibrosis based on histopathological data, one of the most used is the METAVIR score [7]. This system consists of four stages: F0 indicates no fibrosis, F1 is mild fibrosis characterized by fibrous portal expansion, F2 is moderate fibrosis with few bridges or septa, F3 is severe fibrosis with numerous bridges or septa and F4 is cirrhosis [8].
Liver biopsy is the most specific test to assess the nature and severity of the chronic liver disease, but it is an invasive procedure, not free from possible complications so it can not be used to monitor the progression of the disease or to evaluate the effect of therapy on the fibrotic process. Also, the biopsy sample represents 1 / 50,000 of the total liver mass while fibrosis is a heterogeneous process [9].
For these reasons, to date, the number of liver biopsies to evaluate liver stiffness degree is greatly reduced in favor of non-invasive techniques as Fibroscan. However Fibroscan has some limitations, it does not allow a simultaneous ultrasound evaluation of the liver, it has a limited liver scanning and it is contraindicated in patients with obesity or ascites [9].
In elastosonography, the possibility of performing a simultaneous ultrasound evaluation allows a wider sampling of the liver parenchyma and, being fibrosis a heterogeneous process, this could provide a more correct data of the liver fibrosis degree.
As already mentioned, elastography is composed of two basic methods: Strain Elastography and Shear Wave Elastography. The first is a relative indicator of stiffness, that changes according to the degree of compression, besides strain imaging is essentially qualitative, for its quantification requires a comparison with a reference tissue [4]. Shear-Wave based techniques measure the speed of Shear-waves in tissues. The Share-waves can be generated by an external push (transient elastography) or by an ultrasound pulse that allows a single measurement (point shear wave speed measurement) or an image (shear wave speed imaging) [5].
In our study, we evaluated the concordance between TE and the other SWE technique obtained with two US machines.
Results of our study showed that there was no statistically signif- so that more patients could not be enrolled. However a total of 118 assessments were performed and patients were enrolled after evaluation of histological data to have homogeneity of the different degrees of fibrosis; moreover, we think that the evaluation of 11 healthy subjects can improve the results of the work and partially the limit of the small study population.
In conclusion, ours is an attempt to identify the threshold values for different degrees of liver fibrosis with SWE techniques. Our experience confirms that the SWE techniques have good potential in assessing liver fibrosis; moreover, as the elastosonography is quick and easy to perform, it could be integrated into the clinical practice of the ultrasound examination for the evaluation of liver stiffness degree without a significative increase of time of the exam. However, we believe that further studies on elastosonography techniques are applicable to identify more accurate threshold values for the different stages of liver fibrosis.