Development and Validation of a Novel Fibrosis Marker in Biliary Atresia during Infancy

Abstract

Objectives: Most biliary atresia (BA) patients suffer from liver fibrosis and often require liver transplantation. The aim of this study was to develop and validate a novel fibrosis marker for BA patients aged <1 year-the infant BA liver fibrosis (iBALF) score-subsequent to the previously reported fibrosis marker for BA patients aged ≥1 year.

Methods: From three institutions for pediatric surgery, BA patients and their native liver histology examinations performed at the age of <1 year were retrospectively identified and assigned to a development cohort (58 patients and 73 examinations) or validation cohort (92 patients and 117 examinations) according to their institutions. Histological fibrosis stages (F0-F4), blood test results, and clinical information at the time of liver histology examination were reviewed. The iBALF score was determined using multivariate ordered logistic regression analysis and was assessed for its associations with histological fibrosis stages.

Results: The iBALF score equation was composed of natural logarithms, including serum total bilirubin level, blood platelet counts, and days of age. The score revealed a strong correlation with fibrosis stage (r=0.80 and 0.73 in the development and validation cohorts, respectively; P<0.001). The areas under the receiver-operating characteristic curves for diagnosing each fibrosis stage were 0.86-0.94 in the development cohort and 0.86-0.90 in the validation cohort (P<0.001), indicating good diagnostic power. In addition, no patient with an iBALF score >6 (equivalent to F4) at the initial surgery survived with their native liver at 1 year of age (n=9).

Conclusions: The iBALF score that was developed was a good noninvasive marker of native liver fibrosis for BA patients aged <1 year.

Figure 1

Timing of the patients' participation and tissue sampling in the development and validation cohorts. The number was counted after excluding two and three patients with biliary atresia splenic malformation syndrome from the development and validation cohorts, respectively.

Figure 2

Values of the infant biliary atresia liver fibrosis (iBALF) score and aspartate aminotransferase-to-platelet ratio index (APRI) according to the histological fibrosis stages. Boxplots show the median values with the interquartile ranges, and error bars indicate the smallest and the largest values within 1.5 box-lengths of the upper and the lower quartiles. Circles represent the individual points for outliers. Correlations between the markers and the fibrosis stages were evaluated using the Spearman correlation coefficient (r); *P<0.001.

Figure 3

Receiver-operating characteristic curves of two fibrosis markers for diagnosing each fibrosis stage. Evaluated noninvasive markers included the infant biliary atresia liver fibrosis (iBALF) score (thick lines) and the aspartate aminotransferase-to-platelet ratio index (APRI, dashed lines). Gray lines indicate the reference lines. The diagnostic power of each marker was assessed by calculating the area under the curve (AUC); *P<0.001, **P=0.01. The P values in the panels represent the differences between AUCs of the iBALF score and the APRI using the DeLong test.

Figure 4

Relationships between the infant biliary atresia liver fibrosis (iBALF) score at the initial surgery and prognosis. Triangles indicate the patients receiving liver transplantation as the initial surgery. Crosses represent the patients requiring liver transplantation after bile drainage surgery before 1 year of age. The square indicates the patient who died after bile drainage surgery. The patients who survived with their native liver at 1 year of age are expressed by lines between the iBALF score at the bile drainage surgery and the biliary atresia liver fibrosis (BALF) score at 1 year of age.