Feasibility study and reference values of FibroScan 502 with M probe in healthy preschool children aged 5 years

Liver biopsy is traditionally considered the gold standard for diagnosis of hepatic steatosis and fibrosis, but its use as a screening tool in apparently healthy individuals is limited because of its costly and invasive nature, sample errors, and intraobserver and interobserver variability [1‐3]. Recently, some novel noninvasive techniques for assessment of liver fat and fibrosis have been developed. Transient elastography (TE) is one of these new techniques based on inducing a shear wave to the liver and measuring the velocity of the wave. The device (FibroScan-502, Echosens, Paris, France) was developed using the TE technique, and controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) can be obtained simultaneously by the device in a rapid, noninvasive, reproducible and painless way.

FibroScan-502 with M-probe has been widely used in adults with chronic liver diseases and during health examinations, and the CAP and LSM values were found to be closely related to liver biopsy-proven steatosis and fibrosis, respectively [4‐9]. However, FibroScan-502 with M-probe has seldom been used in assessment of liver fat and fibrosis in pediatric individuals with liver diseases, and the reference values of CAP and LSM have not yet been studied well in a large sample of preschool healthy children [10‐14]. Therefore, this study explored the feasibility of this technique with M probeto determine the normal range and factors associated with CAP and LSM values in preschool children aged 5 years from the Shanghai Prenatal Cohort, Shanghai, China.

This study is by far the largest survey using FibroScan-502 with M probe in preschool children who underwent healthy checkups each year from birth. The mean values of LSM, median values of CAP and the ranges of LSM and CAP values in a total of 436 healthy children at 5 years old were obtained in the study.

After the development of TE for more than ten years, FibroScan has been applied in many studies to evaluate adult liver disease [4‐9]. Currently, FibroScan is recommended in many countries and areas as a routine diagnostic for liver fibrosis [16, 17]. CAP is now increasingly used to compensate for the role of liver biopsy in the evaluation of hepatic steatosis [7‐9]. In recent years, FibroScan has also been applied in studies focusing on the diagnosis and follow-up of pediatric liver diseases, mainly concentrating on biliary atresia [10, 18] and chronic liver disease [11‐13]. In addition, many studies on the normal ranges of LSM and CAP in a large sample of healthy children with different ages have already been undertaken. Cho et al. found that the mean value of LSM measured by FibroScan in healthy infants was (3.9 ± 0.9) kPa [15]. Goldschmidt et al. also found that the mean value of LSM was 4.5 (2.5–8.9) kPa by evaluating 527 healthy children (age 0.1–17.8 years, the average age 6.0 years) without any basic diseases [19]. Tokuhara et al. determined the LSM and CAP values in 123 children (age 1–18 years) using FibroScan, and the final results showed that there were significant differences of the mean values of LSM between each age group (p = 0.001), with 3.4 (2.3–4.6 kPa) in children aged between 1 and 5 years, 3.8 (2.5–6.1) kPa in children aged between 6 and 11 years and 4.1 (3.3–7.9) kPa in children aged between 12 and 18 years, respectively, and the mean CAP value was 183 (112–242) dB/m which did not change with age [20]. They thus concluded that the LSM values increased with age. Engelmann et al. also reported that the LSM values increased with age [21]. However, those studies were focused on children with liver diseases or healthy children at different ages, and most studies only measured LSM values without CAP values. As LSM values increased with age, we believe that age could lead to variations in the diagnostic accuracy of TE in a screening setting for hepatic fibrosis and steatosis in apparently healthy individuals [22, 23]. As CAP values were also important for children to identify fatty liver diseases, the normal LSM and CAP values in children at every age should be determined distinctively. Our study used FibroScan to evaluate 436 children (age 58–62 months) of the Shanghai Prenatal Cohort who underwent healthy checkups between August to November 2017. The mean LSM and median CAP values were 3.28 kPa and 171.50 dB/m, respectively. The ranges of LSM and CAP values in our preschool children aged 5 years were 2.00–4.78 kPa and 154.21–214.53 dB/m, respectively.

The FibroScan probe types include S type (S1 and S2), M type and XL type according to the different detection populations. Previous studies and the manufacturer have suggested that the S type probe should be used in preschool and primary school children, whose thoracic circumferences are less than 75 cm [19, 24]. However, it is worth mentioning that the studies that have evaluated the usefulness of TE in children [11, 12] so far have largely been performed in school-age children, using the M(adult) probe [13]. Pradhan et al. found that the S2 probe overestimates the stage of fibrosis compared with the M probe in 10% of patients by evaluating 59 subjects with a thoracic perimeter ≤75 cm, and they believed that the FibroScan M probe should remain the preferred tool for LSM determination in small adults with chronic liver disease [11]. Our study also used the M probe to complete all evaluation in the participating healthy checkup. The total success rate reported in our study was 96.5% which was similar to published adult data [19, 25], but clearly higher than those reported in the pediatric studies by Engelmann et al [21] and Cho et al. [15] The high success rate in our study could be explained by several reasons, such as the parents’ education levels, the small age range and the good degree of cooperation from children and their families. Therefore, if one health center could not afford both the M probe and the S probe considering the total cost, our study results showed that the M probe was also appropriate for detection in these children with correct operation and assurance of accurate results.

In our study, the potential influence of gender on LSM and CAP values using FibroScan was also investigated. The results indicated that the LSM and CAP values did not differ according to gender, which is the same result as reported in other similar studies [19, 20, 26, 27]. Interestingly, there was no correlation between LSM values and all of various demographic, anthropometric, and clinical factors in our anticipating children. However, the situation is different in CAP values. In the univariate analyses of our study, the CAP values were significantly positively correlated with anthropometric measurements (body weight, BMI, waist circumference, fat mass and the percent of body fat), which indicated that CAP values may become a useful tool to assess hepatic fat content and remins doctors to pay attention to apparently healthy children without evidence of sonographic or laboratory abnormalities.

There are some limitations in this prospective study. First, this was a single-center study that included only a sample of preschool children aged 5 years in apparently good health. Further multi-center large study with large sample preschool children are needed, which will validate the normal ranges of LSM and CAP values and consider some other factors. Second, our study was focused on apparently healthy children who did not undergo liver ultrasound and liver biopsies, although liver ultrasound was not recommended for the diagnosis of fatty liver in children considering its lack of sensitivity and specificity, and liver biopsies are also not appropriate for healthy children. Third, this study only focused on an age level. We should continue to discover the normal range at other age levels in future studies based on this ongoing perspective birth cohort.

In conclusion, these promising results supported FibroScan epuipped with M probe can be used to measure LSM/CAP values in the preschool children aged 5 years. The success rate was similar to that in adult. This study also determined the normal ranges of LSM and CAP values in Chinese 5-year-old children which are different from these in adults. CAP values may become a useful tool to access hepatic fat content in children. Further follow-up with this Shanghai Prenatal Cohort and further study with other large sample sizes are needed to validate the normal ranges of LSM and CAP values at different age levels and whether LSM and CAP can identify those children who are at a higher risk of subsequently developing NAFLD.