A girl neonate weighing 1590 g was born at 31 weeks of gestation. There was no peculiar familial medical background, and antenatal ultrasonographies were normal. She developed neonatal respiratory distress and hypoxia due to a hyaline membrane disease. APGAR score was 6 at 1 minute and 8 at 5 minutes. Feeding with premature formula was tolerated and she did not receive parenteral nutrition. She was jaundiced 2 days after birth, but stools were normally colored. She was referred to our unit for diagnostic workup of neonatal jaundice and suspicion of cholestasis. At the admission, 45 days after birth, she still was jaundiced and stools were alternatively normally colored and slightly discolored. Liver was slightly enlarged and serum liver tests showed cholestasis (Table 1). Total serum bile acid concentration was increased (76 μmol/L). The main causes of neonatal cholestasis other than BA were excluded (9,10). Abdominal ultrasonography (high-frequency transducer, 12 MHz) showed a small anechoic cyst (4 × 6 mm) located at the porta hepatis (Fig. 1B). The ultrasonographic “triangular cord” was not observed (11). Bile ducts were not dilated and the main bile duct was not visible. The gallbladder was not visible. There was no sign of BASM. This aspect was suggestive of BA, but stools remained normally colored. A magnetic resonance cholangiography was performed, but did not provide any more valuable information (12). Progressively, stools discolored and became acholic 9 weeks after birth (corrected age: 1 day). A laparotomy was performed 10 weeks after birth (corrected age: 1 week). Intraoperative cholangiography was in favor of complete BA (type III) and a portoenterostomy was performed. BA diagnosis was confirmed by the histological examination of the biliary remnant. Liver histology showed septal fibrosis, cholestasis, and bile duct proliferation. Stool color was normal 8 days after surgery. Serum bilirubin level decreased and normalized 1 month after surgery. The child received a symptomatic treatment for cholestasis including ursodeoxycholic acid. After 6 months, stools remained normal, as did the serum total bilirubin level. Three years after the Kasai operation, the serum total bilirubin concentration was normal (Table 1).
In premature neonates, cholestasis is often multifactorial in origin and related to risk factors such as anoxia, ischemia, immaturity of bile acid metabolism/enterohepatic circulation, genetic predisposition, infection, lack of enteral feeding, necrotizing enterocolitis, and/or prolonged total parenteral nutrition, in the context of perinatal distress (9,10,13). Such cholestasis is usually spontaneously resolving within a few months and is classified as “transient neonatal cholestasis,” which implies that all of the other causes of neonatal cholestasis have been excluded (14). Its prognosis is good, and in most cases, stools are not acholic. Nevertheless, BA may be associated by chance with perinatal distress, and the latter should not be used as an argument to overdiagnose transient neonatal cholestasis. Our report illustrates this point, showing that in preterm neonates with cholestasis, in fact related to BA, discoloration of stools can occur several weeks after birth, whereas initial hepatic ultrasonographic findings may already indicate BA (15). In preterm children reported here, the first trap that has been avoided was to consider that the babies did not have cholestasis because initial conjugated bilirubin represented only around 15% (>17 μmol/L) of serum total bilirubin concentration and stools were yellow. In a jaundiced neonate with normally colored stools, it is a rule to consider cholestasis when the serum conjugated bilirubin concentration is either >17 μmol/L or >20% of serum total bilirubin concentration; all the more that other serum liver test parameters are abnormal, including γ-glutamyl transferase activity and total bile acid concentration (1,9,16). The second trap that has been avoided was to consider that these babies did not have BA because stools were initially normally colored, at a time corresponding to the last weeks of a full-term pregnancy. In both preterm babies, stools became acholic at a time corresponding to a normal term birth (corrected age: 1 day). This is in accordance with previous data, which showed that in normal-term babies with BA, stools became acholic within 2 weeks after birth (17). The third trap that has been avoided was to interpret favorably the decrease in total serum bilirubin concentration, whereas the proportion of conjugated bilirubin increased signing cholestasis. The fact that the main medical causes of neonatal cholestasis were excluded suggested BA, all the more that liver ultrasonography identified early signs highly suggestive of BA (9,10,15). Surgical and histological findings obtained at a corrected age of 1 week were typical of BA. Although the presence of early cholestasis in these preterm neonates with BA suggests that bile duct injury has started before or during the third trimester of pregnancy, the precise timing of the onset of the injurious process cannot be determined (4–6). It has been emphasized recently that increased age at Kasai operation has a negative effect on the long-term outcome of children with BA (2). Indeed, survival rates with native liver increased when age at surgery decreased, the best rate being obtained when the Kasai operation is performed before age 31 days. In preterm neonates reported here, surgery was performed early, at a corrected age of 1 week, and both children were alive with their native liver with almost normal or normal serum total bilirubin levels at age 3 years. Although neonates with BA may benefit from early Kasai operation, surgery should be performed after 2 weeks of life and complete umbilical cord healing because in our experience severe sepsis due to omphalitis may complicate surgery performed too early (unpublished data). These cases illustrate that diagnosis of cholestasis in preterm jaundiced neonates is difficult and that careful workup and follow-up is mandatory to detect BA.
We thank Drs Belzic (Lorient, France) and Suc (Tours, France) for referring the patients to our unit.
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