Risk factors for severe liver fibrosis in children with CFLD in a multicenter study validated by liver biopsy

Abstract

Introduction: Early identification of risk factors for the development of severe fibrosis in children with cystic fibrosis-related liver disease (CFLD) is crucial as promising CFTR modulator therapies emerge. Few liver biopsy validated studies exist. Objectives: To evaluate the clinical utility of biomarker indices, clinical characteristics and laboratory parameters in pediatric CFLD to predict risk of developing severe fibrosis (F3-4). Methods: This was a multicenter cohort study of children with CFLD (≥2: hepatomegaly ±splenomegaly; >6 months elevation of ALT (>1.5x ULN); fibrosis on liver biopsy; abnormal liver ultrasound findings) and liver histology (biopsy or explant) from September 1999 to November 2016. Baseline clinical features, labs, calculated APRI, FIB-4, GGT to platelet ratio (GPR), and anthropometrics were collected a median of 2.1 years prior to biopsy. Liver fibrosis was staged by Metavir classification. A Wilcoxon rank sum test was used to compare differences between fibrosis stage F0-2 (mild) vs F3-4 (severe). Logistic regression was used to evaluate specific variables to predict F3-4 fibrosis and product-limit survival estimates were used to determine how characteristics impacted time to F3-4 fibrosis. Results: The study cohort (n=42) was 57% male with a median age of 7.6 years at baseline and 10.3 years at biopsy. Fibrosis groupings were F0-2 (n=22) and F3-4 (n=20). Median FEV1 % predicted was lower (64%, p=0.029) in F3-4 patients at baseline compared to F0-2 (87.1%). The following markers (median) were higher in F3-4 vs F0-2 at baseline: FIB-4 (0.23 vs 0.11; p=0.03), APRI (0.5 vs 0.28; p=0.004), GGT (59.5 vs 18; p=0.002) and GPR (0.21 vs 0.06; p<0.001). Cutoffs for FEV1 , platelets, FIB-4, APRI and GPR were associated with more rapid progression to F3-4: FEV1 <74% (1.05 years vs 9.62, p=0.003, 95% CI [0.36, 1.52]); platelets <298.52 x103/μL (1.3 years vs 3.8, p=0.015, 95% CI [0.77, &infin]); FIB-4 ≥ 0.55 (0.96 years vs 3.8, p<0.0001, 95% CI [0.15, 1.52]), APRI ≥ 0.78 (0.96 years vs 3.8, p<0.0001, 95% CI [0.15, 1.52]); and GPR ≥ 0.41 (0.96 years vs 4.5, p<0.0001, 95% CI [0.15, 1.52]). Positive Pseudomonas aeruginosa from a respiratory culture ≥2 years of age progressed to F3-4 more rapidly (2.73 years vs 3.78, p=0.04, 95% CI [0.53, 2.73]) than F0-2. The AUROC of change/year of a combination of FIB-4, APRI, platelets, and GPR was 0.81 (p<0.0001). Conclusion: Children with CFLD who develop F3-F4 fibrosis validated by liver biopsy are unique in clinical characteristics and biomarker indices preceding liver biopsy, up to 2 years prior. FEV1 <74% among CFLD dichotomized those who would progress to F3-4, 9-fold more rapidly. These lab and biomarker differences may assist in cohorting patients with CFLD as more likely to develop severe fibrosis, allowing for earlier surveillance and intervention.L6293886432019-09-26 <br />