New Studies on Diagnosing and Managing Pediatric Liver Diseases

William F. Balistreri, MD


December 21, 2018

In This Article

Predictors of Outcome in Children with Biliary Atresia

Venkat and colleagues[11] aimed to identify biochemical and clinical predictors of outcome in children with biliary atresia surviving with their native liver at 2 years of age. They interrogated data from children enrolled in the Childhood Liver Disease Research Network (ChiLDReN), a longitudinal, prospective registry. Of 1300 participants with biliary atresia in the registry, 263 were enrolled at age ≤ 2 years, had their native liver at age 2 years, and were followed yearly thereafter. Median follow-up was 3.1 years. Forty-three patients either underwent liver transplant (n=41) or died (n=2) at a median age of 2.9 years. Twenty-three patients experienced a sentinel event consisting of new-onset ascites, hepatopulmonary syndrome, or variceal bleeding. The investigators identified total serum bilirubin, albumin, and AST to platelet ratio index (APRI) value at age 2 as the strongest lab predictors of transplant or death. Variceal bleeding was the strongest clinical variable predicting transplant or death, with a hazard ratio (HR) of 6.65. Platelet count and APRI at age 2 were the strongest predictors of the first sentinel event. Linear growth failure at age 2 predicted a greater risk for a sentinel event than any other clinical parameter (HR, 3.91).

Although persistently elevated total serum bilirubin predicts poor outcomes after Kasai portoenterostomy for infants with biliary atresia, achieving normal total bilirubin does not uniformly lead to good long-term outcomes. Hence, additional prognostic markers are needed. Harpavat and colleagues assessed whether the total serum bile acid (TSBA) level, measured 6 months after Kasai portoenterostomy, was predictive of later liver injury, portal hypertension, or need for liver transplant.[12] They found that the TSBA level correlated positively across all total bilirubin values; however, TSBA levels varied widely (from 4 to 2378 µmol/L) when the total serum bilirubin level was <1.5 mg/dL, raising the possibility that TSBA can discriminate outcomes when total bilirubin normalizes. To examine this further, patients with biliary atresia were divided into those with low and high TSBA levels 6 months post-Kasai portoenterostomy. Lower TSBA levels were associated with ALT ≤40 U/L, GGT ≤55 U/L, platelet count ≥150, and smaller spleen size at 2 years of age. In addition, all participants with lower TSBA levels survived transplant free, compared with only 72% of participants with higher TSBA levels. When all TSBA levels obtained >6 months post-Kasai portoenterostomy were considered, lower levels correlated with earlier Kasai portoenterostomy, faster total bilirubin normalization, less liver injury, and portal hypertension at 2 years, as well as a possibly lower future need for liver transplant. These results suggest that lower TSBA levels may be a powerful prognostic marker after successful Kasai portoenterostomy and a potentially important endpoint in future biliary atresia therapeutic trials.

Finally, Luo and colleagues[13] investigated whether clinical, biochemical, and gene expression profiles predict clinical outcome. Global gene expression was quantified by RNA sequencing of liver biopsies obtained from 171 infants with biliary atresia at the time of diagnosis. To test the hypothesis that the transcriptome contains gene signatures predicting clinical outcome, they applied principal component for Cox regression and survival analyses and uncovered 14 genes that divided the discovery cohort into groups of low or high survival with the native liver at 2 years.

When combined with total bilirubin levels 3 months after Kasai, the gene signature reliably predicted low and high survival at a discriminatory performance of 0.948 in the discovery and 0.813 in the validation cohort. Functional analysis of the genes showed a prominent activation of extracellular matrix and inflammation in the low-survival group. Inference modeling linked fibrosis to the abundance of stellate cells, portal fibroblasts, cholangiocytes, CD8 T and natural killer (NK) cells, with highest correlations between NK cells and either stellate cells or portal fibroblasts. The expression signatures also identified oxidative stress due to a suppression of the glutathione biosynthesis pathway and overexpression of oxidases and TGFB1 in the low-survival group. Thus, this gene expression signature at diagnosis predicts survival with the native liver at 2 years of age. Low-survival livers are enriched for NK and matrix-producing cells with evidence of oxidative imbalance.

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