Shear Wave Elastography in the Assessment of Liver Changes in Children with Cystic Fibrosis

*Mikhail Pykov, Natalia Kuzmina and Nikolay Rostovtsev*

### **Abstract**

A standard ultrasound examination of the liver was performed in 232 children. It was supplemented by a two-dimensional shear wave elastography. There were 200 healthy children aged 3 to 18 years (control group) and 32 patients with cystic fibrosis aged 2 to 17 years (study group) among them. The procedure was carried out by means of Aixplorer device (Supersonic Imagine, France) using a convex sensor operating in the 1–6 MHz frequency range. Ten measurements of Young modulus values were carried out in different segments of the right lobe of the liver followed by data averaging. In patients with cystic fibrosis, the values of Young modulus were significantly higher than in healthy children (Emean median: 6.50 and 5.00 kPa, interquartile range: 5.62–7.52 and 4.70–5.38 kPa, respectively (p < 0.001). In patients with severe cystic fibrosis, the values of Young modulus were significantly higher compared to patients suffering from moderate disease (Emean median: 7.30 and 5.90 kPa, interquartile range: 6.20–10.70 and 5.20–6.75 kPa, respectively (p < 0.002). Shear wave elastography is a non-invasive technique that can be successfully used in a comprehensive ultrasound assessment of the liver in children with cystic fibrosis to facilitate the diagnosis and monitoring of fibrous changes.

**Keywords:** ultrasound elastography, shear wave elastography, stiffness, young modulus, cystic fibrosis, fibrosis, liver, children

### **1. Introduction**

Recently, ultrasound elastography has become perhaps the most important achievement in the evolution of non-invasive techniques, particularly ultrasound examination, to assess the condition of the liver in general. This is a method of qualitative and quantitative analysis of elastic properties of tissues, which makes it possible to evaluate the elastic properties of tissues during a conventional ultrasound examination by measuring the values of shear wave velocity (m/s) or Young modulus (kPa) in the organs and tissues of interest [1].

As a rule, the stiffness in pathological tissues is more pronounced compared to the adjacent healthy tissues, and this fact is registered by ultrasound elastography of different types. According to the international guidelines, ultrasound elastography methods are divided into compressive elastography (SE) and shear wave elastography (SWE) [2–5]. SWE methods measure the velocity of shear waves generated in the tissues by an external mechanical shock (transient elastography, TE) or an electronic impulse (ARFI). The advantages of ARFI-based elastography methods (point elastography, pSWE and two-dimensional elastography, 2D-SWE) are that they are fast and integrated into the ultrasound diagnostic system, which enables to perform grayscale navigation. When conducting 2D-SWE, we get not only quantitative data in the form of digital values of the shear wave velocity but also qualitative information, since the areas with different values of the Young modulus are mapped in different colours. It is the digital values of indicated parameters that determine the colour in the area of interest [1, 6].

Most guidelines and recommendations for the clinical use of elastography (EFSUMB, WFUMB) focus on the assessment of diffuse liver disease in adults [2–9]. However, recommendations for adult patients cannot be immediately used in paediatric practice, taking into account the peculiarities of paediatric patients, i.e., restless behaviour during the examination of young children, small intervals between meals in infants, difficulties with breath-holding. These factors can affect the reproducibility of measurements and the accuracy of diagnostics in paediatrics. Psychological, anatomical and morphological features of children make the technique of elastography even more complex than a conventional ultrasound examination. Therefore, ultrasound elastography is less studied in children than in adults. Nevertheless, there are more and more reports from different research groups about the use of elastography to assess liver stiffness in healthy children. Special attention is paid to the age and gender characteristics of stiffness, the dependence of values on body mass index, use of sedatives and food intake. The technique of the procedure is discussed concerning the position of the patient during the examination, the choice of the sensor, the zone and the number of measurements, the ambient conditions during the procedure. There are also works where elastography is used in the assessment of the spleen, thyroid gland, renal parenchyma, intestines and muscles [6, 10–13].

Numerous studies in adult patients have demonstrated that ultrasound elastography is a useful non-invasive method for diagnosing liver fibrosis. Preliminary findings using TE, pSWE and 2D-SWE have also shown that they are all feasible and can be used to assess liver fibrosis of various aetiology in children [6, 10, 11, 13]. Various infectious agents can act as an etiological factor causing fibrosis and cirrhosis of the liver in children, such as hepatitis B, C, D, G viruses, cytomegalovirus, Epstein-Barr virus, as well as autoimmune liver diseases, cystic fibrosis, metabolic diseases and others. Regardless of the aetiology, cirrhosis results in lethal outcome of patients due to the development of complications, i.e., bleeding from the oesophageal varices, ascites, encephalopathy, hemorrhagic syndrome.

Liver biopsy, being an invasive procedure, is less acceptable for children due to the need for general anaesthesia, as well as physical and emotional impact on the child. This procedure can cause a number of complications, such as pain syndrome, profuse bleeding, formation of subcapsular hematomas of the liver, development of biliary peritonitis, etc. [14, 15]. Non-invasive methods are extremely important in paediatrics, especially when repeated examinations are necessary, for example, during follow-up of patients with chronic liver diseases, when elastography can be used additionally to ultrasound examination and laboratory data facilitating observation of children with chronic liver diseases [10, 11, 13].

#### **2. Pathophysiology of fibrotic changes in the liver in cystic fibrosis**

Cystic fibrosis is one of the most common monogenic diseases with an autosomal recessive type of inheritance and multiple organ manifestations. In most countries of

#### *Shear Wave Elastography in the Assessment of Liver Changes in Children with Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.103185*

Europe and North America, cystic fibrosis prevalence ranges from 1:2,000 to 1:4,000 newborns, in Russia, it is 1:8000–1:10,000 newborns. The disease is caused by the gene mutation of the transmembrane regulator of cystic fibrosis and is characterised by damage to the external secretion glands and severe respiratory disorders. However, due to the increased life expectancy of patients with cystic fibrosis, liver damage becomes an important clinical manifestation that determines the prognosis and quality of life [16–18].

Cystic fibrosis is no longer considered exclusively a childhood disease since the current life expectancy of such patients is more than 35 years [19]. According to different authors, the incidence of clinically apparent liver lesions in cystic fibrosis (cystic fibrosis-associated liver disease – CFLD) varies from 27 to 35% [18]. Symptoms of liver fibrosis of varying degrees are revealed in almost all patients with cystic fibrosis, and 5–10% of patients develop biliary cirrhosis of the liver with portal hypertension syndrome requiring surgical intervention [20, 21]. In the general list of causes of death in cystic fibrosis, liver cirrhosis is in the second place after bronchopulmonary complications and is 2.3–2.5% [20, 22].

The hepatobiliary system failure in cystic fibrosis is a direct consequence of a basic genetic defect. The CFTR protein is responsible for the pathogenesis functions as a channel of chloride ions [20, 23]. Insufficiency of the function of the channel of chlorine ions of cells lining the intrahepatic and extrahepatic bile ducts and gallbladder results in dehydration of hepatic secretions, i.e., they become adherent and poorly soluble [24]. Consequently, hepatocellular and canalicular cholestasis develops, which leads to a number of undesirable reactions, namely, delay of hepatotoxic bile acids, production of inflammatory mediators, cytokines and free radicals, increased lipid peroxidation and damage to cellular membranes, an excessive inflow of bile into the blood and tissues [25]. According to the clinical and morphological principle, liver cirrhosis in cystic fibrosis refers to biliary cirrhosis with obstruction of the intrahepatic biliary tract; microscopically – to multilobular cirrhosis; according to etiological characteristic – to cirrhosis caused by genetic metabolic disorders. Liver damage is characterized by chronic inflammatory cell infiltration and bile duct proliferation. These alterations are initially of a limited focal nature, but then they progress and lead to multilobular cirrhosis and portal hypertension. The process can slowly develop without pronounced clinical and biochemical manifestations, but it is irreversibly progressing [21–23, 26].

To date, there is no consensus on the risk factors and the rate of development of fibrotic liver changes in cystic fibrosis. Prematurity, low birth weight and prolonged parenteral nutrition are indicated as the causes of cystic fibrosis progression. Also, the severity of liver damage is associated with recurrent sepsis (including catheter sepsis) and bacterial load. Although it is believed that liver damage is more common in patients with severe mutations pertaining to classes I– III, genotype-phenotype correlation, which predicts the effect of mutation on the clinical expression of CFLD, is not possible at this stage. So, the clinical course in patients with diagnosed cystic fibrosis and the same mutation of the CFTR gene may be different [27]. It is still unclear why only a small number of patients with the same severe mutations develop CFLD symptoms. Some authors consider age at the time of diagnosis, male gender, intestinal obstruction of meconium in the anamnesis, external secretory insufficiency of the pancreas to be important factors [28, 29].

Early diagnosis of liver damage is complicated by a prolonged subclinical phase and lack of a reliable diagnostic technique: biochemical indices of liver failure

(increased bilirubin level, decreased albumin concentration and increased prothrombin time) appear late, when severe liver failure has developed. Therefore, all patients with cystic fibrosis should be carefully monitored for the occurrence of this complication in the first decade of their life [18, 25, 26]. Regular examination of patients, biochemical tests and imaging methods of examination are of utmost importance. At the same time, a normal ultrasound picture cannot exclude the presence of fibrosis [30].

Despite the high informativeness of morphological methods, diagnostic liver biopsy for all patients with cystic fibrosis, and especially performed repeatedly, cannot be justified, primarily because of its traumatic nature. In addition, due to inhomogeneous liver damage, a biopsy may underestimate the severity of the lesion. The procedure is indicated when the diagnosis is doubtful or to confirm the findings before liver transplantation [17, 20].

That is why the efforts of researchers are aimed at finding such diagnostic non-invasive methods (especially important in paediatric practice), which will be informative, accessible, capable of detecting liver changes and carrying out dynamic monitoring of the fibrous process. The use of shear wave elastography in the early diagnosis of liver diseases in patients with cystic fibrosis becomes particularly relevant since a number of authors point to the reversible nature of such conditions as fatty hepatosis and cholestasis following treatment [17, 25]. The aim of our investigation was to study the stiffness of the liver using shear wave elastography in children suffering from cystic fibrosis.
