New Studies on Diagnosing and Managing Pediatric Liver Diseases

William F. Balistreri, MD


December 21, 2018

In This Article

Biliary Atresia

Children with biliary atresia, a progressive fibro-obliterative disease of the extrahepatic bile duct that affects neonates, represent a major clinical challenge. The diagnosis of biliary atresia remains a clinical challenge owing to substantial overlap in clinical and biochemical features with other causes of neonatal cholestasis. In addition, there is no effective therapy. A surgical effort to establish bile flow through creation of a hepatoportoenterostomy (Kasai procedure) has been the standard approach. However, biliary atresia remains the major indication for liver transplantation in children. As a final challenge, there is currently no prognostic model for the natural history of patients with biliary atresia surviving with their native liver. Although both age at diagnosis and response to surgery have been correlated with improved survival, biological predictors of outcome are undefined. The quest for a diagnostic biomarker is dependent upon an understanding of the initiating and perpetuating mechanisms.

What Is the Mechanism of Bile Duct Injury?

Lorent and colleagues[7] previously identified a toxin, biliatresone, that is responsible for large outbreaks of biliary atresia in neonatal livestock (sheep) after maternal exposure. To further understand the mechanism, Wehrman and colleagues[8] tested the hypothesis that biliatresone treatment of pregnant mice would lead to extrahepatic bile duct injury in neonatal offspring, and that this injury may be potentiated by bile acids. Timed pregnant mice were treated with biliatresone by gavage for 2 days starting at gestational age 14. One group was fed chow with 0.3% glycochenodeoxycholic acid (GCDC) starting at gestational day 7 and until weaning. Pups from mothers treated with biliatresone and fed standard chow had disruption of the extrahepatic bile duct cholangiocyte monolayer and mild submucosal fibrosis at day 7, which was not seen at day 21. Pups from mothers treated with biliatresone and fed GCDC-fortified chow had similar bile duct damage at day 7, although there was persistent disruption of the extrahepatic bile duct with submucosal fibrosis at day 21. Weights of pups in both groups were similar at day 7, but at day 21 pups from mothers fed GCDC-fortified chow were on average 4.3 g smaller compared with those fed standard chow. Pups from mothers fed GCDC-fortified chow alone and not treated with biliatresone appeared to have normal extrahepatic bile ducts at day 7. Of note, the liver and the extrahepatic bile duct appeared normal in the mothers of both groups. The investigators suggest that extrahepatic bile duct damage in this model of biliary atresia may represent a "two-hit phenomenon" and underscores the importance of bile acid toxicity in the progression of bile duct damage. They postulate that alteration of the bile acid pool in the neonatal period may be a potential target in efforts to halt progression of biliary atresia.

A Biomarker for Extrahepatic Bile Duct Injury?

Matrix metalloproteinase-7 (MMP-7) is an enzyme expressed in bile duct epithelium. Yang and colleagues[9] sought to determine whether an elevated serum concentration of MMP-7 is diagnostic for extrahepatic bile duct injury, specifically in patients with biliary atresia. They enrolled 189 infants into an observational study in three major pediatric centers in the city of Wuhan, China. The study population consisted of 75 infants with biliary atresia, 60 age-matched infants with intrahepatic cholestasis, and 54 without liver disease. The concentration of MMP-7 in serum samples obtained at the time of diagnosis was quantified using an antibody-based ELISA kit. The ultimate diagnosis of biliary atresia was made by the direct visualization of obstruction via an operative cholangiogram and histologic evidence of a fibrosed lumen in the biliary remnants. The serum MMP-7 concentration was distinctly elevated at the time of diagnosis of biliary atresia, with high sensitivity and specificity to differentiate biliary atresia from other causes of neonatal cholestasis. The median MMP-7 concentration in patients with biliary atresia was 121 ng/mL, which was higher than that noted in patients with intrahepatic cholestasis (12 ng/mL) and normal controls (3 ng/mL). The AUC for patients with biliary atresia using MMP-7 was 0.99 compared with 0.72 for serum gamma-glutamyl transferase (GGT). With a minimal overlap with intrahepatic cholestasis or controls, and at a cutoff value of 53 ng/mL, the diagnostic sensitivity and specificity of MMP-7 for biliary atresia was 99% and 95%, respectively, with a negative predictive value of 98%.

Also of note from this meeting, Lam and colleagues[10] reported that serum MMP-7 was a novel, noninvasive biomarker of bile duct injury in another pediatric extrahepatic bile duct disease: sclerosing cholangitis. In patients with primary sclerosing cholangitis, immunofluorescence localized MMP-7 to cholangiocytes, and to lesser degree to Kupffer cells and activated hepatic stellate cells, linking MMP-7 to biliary injury and fibrosis. In these patients, serum MMP-7 levels correlated with the presence of periductal sclerosis and lymphocytic cholangitis. Serum MMP-7 levels also correlated with number of biliary strictures and dilatations of the biliary tree as determined by magnetic resonance cholangiopancreatography, and with liver stiffness as assessed by MRI elastography.

These two studies indicate that MMP-7 is a promising biomarker for noninvasive diagnosis of extrahepatic bile duct injury, both biliary atresia and sclerosing cholangitis in children.


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