Assessment of the Severity of Hepatic Fibrosis in Children Based on Direct Biomarkers: a Noninvasive Approach

The aim of the study is to evaluate the diagnostic information value of direct serological biomarkers — hyaluronic acid (HA), collagen types I and III (COL1, COL3), growth differentiation factor-15 (GDF-15), monocyte chemotactic factor-1 (MCP-1) and extracellular matrix protein 1 (ECM1) — for noninvasive stage identification hepatic fibrosis (HF) in children.

Material and methods. The study included 60 patients (average age 10.2 ± 4.7 years) with chronic liver diseases of various etiologies, including autoimmune hepatitis (16), primary sclerosing cholangitis (11), glycogen disease (10), Wilson’s disease (6), and unspecified HF (17). All children underwent ultrasound examination of the abdominal organs with two-dimensional shear wave elastography (2D-SWE) and quantitative determination of the above markers in the blood serum. The concentrations of HA in the blood serum of patients were determined by enzyme-linked immunosorbent assay (ELISA); COL1, COL3, ECM1, GDF-15 and MCP-1 were determined by sandwich ELISA.

Results. The concentrations of HA and GDF-15 in blood serum increased statistically significantly with the progression of HF (p < 0.001; p = 0.001, respectively). To determine the threshold values of HA depending on the stages of HF, high sensitivity (90%) and specificity (up to 100%) were obtained, and the best values of the area under the ROC-curve were used to distinguish the late stages of fibrosis (AUC up to 0.965). The concentrations of GDF-15 in serum are characterized by maximum sensitivity when determining cut-off values to determine the stage of severe fibrosis and its initial manifestations, the specificity for close stages was lower (up to 70%). The concentrations of COL1, COL3, MCP-1, and ECM1 did not show significant differences between the HF stages (p = 0.108; p = 0.455; p = 0.158; p = 0.058, respectively). Direct correlations were found between serum levels of COL1 and COL3 (p = 0.341, p = 0.008), HA and GDF15 (p = 0.592, p < 0.001), MCP-1 and COL3 (p = 0.443, p < 0.001), as well as HA and GDF-15 with the results of 2D-SWE (p = 0.534, p < 0.001; p = 0.505, p < 0.001, respectively).

Conclusion. Determination of HA and GDF-15 concentrations can be considered as a valuable prognostic tool for noninvasive HF stratification in children. The usage of these indicators as part of diagnostic algorithms can help to more accurately determine the stage and dynamics of fibrosis, allowing in some cases to abandon invasive methods such as biopsy.

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