Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

BACKGROUND & AIMS: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters. METHODS: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted. RESULTS: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa. CONCLUSIONS: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.

Normal Liver Stiffness Values in Children: A Comparison of Three Different Elastography Methods.

OBJECTIVES: Noninvasive tests for the evaluation of liver fibrosis are particularly helpful in children to avoid general anesthesia and potential complications of invasive tests. We aimed to establish reference values for 2 different elastography methods in a head-to-head comparison for children and adolescents 4 to 17 years, using transient elastography as common reference in a subset. METHODS: A total of 243 healthy participants aged 4 to 17 years were examined by a single observer with a full liver B-mode scan before elastography, following a minimum of 3 hours fasting. Liver stiffness measurements (LSMs) using 2-dimensional shear wave elastography (2D-SWE, GE Logiq E9) and point shear wave elastography (pSWE, Samsung RS80A with Prestige) were performed in all participants, and compared to transient elastography (TE, FibroScan) in a subset (n = 87). Interobserver agreement was evaluated in 50 children aged 4 to 17 years. RESULTS: Valid measurements were obtained in 242 of 243 (99.6%) subjects for 2D-SWE, 238 of 243 (97.9%) for pSWE, and in 83 of 87 (95.4%) for TE. Median liver stiffness overall was 3.3 (interquartile range [IQR] 2.7-4.3), 4.1 (IQR 3.6-4.7), and 4.1 kPa (IQR 3.5-4.6) for 2D-SWE, pSWE, and TE, respectively. Intraclass correlation coefficients between observers were 0.84 and 0.83 for 2D-SWE and pSWE, respectively. LSM values were significantly lower for 2D-SWE compared to pSWE and TE, and increased with advancing age. Higher LSM values in males were observed in adolescents. CONCLUSIONS: All methods showed excellent feasibility. 2D-SWE showed significantly lower LSM values than pSWE and TE, and lower failure rate compared to TE. Our results further indicate an age and sex effect on LSM values.

Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. METHODS: We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. RESULTS: At baseline, the median (range) ELF test was 9.3 (7.5-12.9) and median LSM 1.26 m/s (0.66-3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). CONCLUSIONS: ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk.