Non-invasive monitoring of liver fibrosis is an unmet and critical need within the clinical management of children with chronic liver disease. While liver biopsy is often used in the initial diagnostic evaluation of children with liver disease, subsequent surveillance liver biopsy is rarely performed in children because of its inherent invasiveness and risks. Therefore, our understanding of the natural history of fibrosis progression in children is limited. The patchy nature of fibrosis in many important pediatric liver diseases (e.g., biliary atresia (BA) and cystic fibrosis liver disease (CFLD)) limits the utility of sequential liver biopsy even if it were to be employed in clinical practice in pediatrics. Thus, non-invasive means of assessing liver fibrosis throughout the liver would be highly desirable and clinically useful in pediatric hepatology. The Childhood Liver Disease Research Network (ChiLDReN) is poised and uniquely qualified to conduct a comprehensive longitudinal assessment of the utility of FibroScan™-specific elastography, liver stiffness measurement (LSM) as a measure of hepatic fibrosis in children with serious chronic cholestatic liver disease.

The FibroScan in Pediatric Cholestatic Liver Disease (FORCE) study, a natural history study within ChiLDReN, was a cross-sectional and longitudinal assessment of the utility of LSM in children with chronic cholestatic liver disease. Study participants were from 13 ChiLDReN sites in the U.S. and Canada, and were also enrolled in the PROBE, BASIC, or LOGIC studies. FORCE participants were evaluated for a period of up to 24 months to assess the non-invasive ultrasound tool (FibroScan™) to detect and quantify global liver fibrosis in children with biliary atresia (BA), alpha-1 antitrypsin deficiency (A1ATD), and Alagille syndrome (ALGS). The participants were non-fasted and non-sedated during data collection. There were three visits in the study: baseline, 12-month follow-up, and 24-month follow-up. Clinical data and specimens were collected at each visit along with repeated FibroScan measurements such as liver stiffness measurements (LSM) to quantify liver fibrosis, and controlled attenuation parameter (CAP) to quantify liver steatosis.

The aim of the FORCE study was to prospectively assess whether FibroScan™ LSM was associated with the clinical and laboratory features of portal hypertension in children with BA, A1ATD, and ALGS, and to prospectively measure changes in LSM over time.

Primary Outcome Measure: Study participants were assessed using FibroScan™ measurements for liver stiffness to quantify liver fibrosis, and controlled attenuation parameter to quantify liver steatosis, from the baseline visit to the 24-month visit. The results were compared between the diagnosis groups.

Secondary Outcome Measure: Participants were also evaluated for laboratory parameters (such as total bilirubin, gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, platelet count, etc.) as part of routine clinical evaluation for children with chronic liver disease.

Inclusion Criteria: Study participants were age 21 years or less at time of enrollment; enrolled in the PROBE, BASIC, or LOGIC studies; willing and able to participate in the study for up to 24 months; and had one of the three following diagnoses (BA, A1ATD, or ALGS).

Exclusion Criteria: Individuals were excluded from participation if they had BA with known situs inversus or polysplenia/asplenia; presence of clinically significant ascites detected at physical examination; open wound near expected FibroScan™ probe application site; use of implantable active medical device (e.g., pacemaker, defibrillator); known pregnancy; prior liver transplant; or unable to give informed consent or assent.

Study outcomes show that it is feasible to obtain LSMs in children, especially over the age of 2 years. LSM correlates with liver parameters and portal hypertension. There was a positive correlation between LSM and total bilirubin, international normalized ratio (INR), AST, ALT, GGT, GGT to platelet ratio (GPR), pediatric end-stage liver disease score, AST to platelet ratio index, and spleen size, and a negative correlation with albumin and platelet count in BA participants. Clinically evident portal hypertension (CEPH) was more common in BA participants than A1ATD and ALGS participants, and LSM was greater in definite versus absent CEPH in all three diseases.