Urinary and serum oxysterols in children: developmental pattern and potential biomarker for pediatric liver disease.

Few reports describe oxysterols in healthy children or in children with liver disease. We aimed to determine whether developmental changes in urinary and serum oxysterols occur during childhood, and to assess whether oxysterols might be biomarkers for pediatric liver disease. Healthy children enrolled as subjects (36 and 35 for urine and serum analysis, respectively) included neonates, infants, preschoolers, and school-age children, studied along with 14 healthy adults and 8 children with liver disease. We quantitated 7 oxysterols including 4ß-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol using liquid chromatography/electrospray ionization-tandem mass spectrometry. Urinary total oxysterols were significantly greater in neonates than in infants (P < 0.05), preschoolers (P < 0.001), school-age children (P < 0.001), or adults (P < 0.001), declining with age. Serum total oxysterols in neonates were significantly lower than in infants (P < 0.05), preschoolers (P < 0.001), school-age children (P < 0.05), or adults (P < 0.01). Compared with healthy children, total oxysterols and 24(S)-hydroxycholesterol in liver disease were significantly increased in both urine (P < 0.001 and P < 0.001, respectively) and serum (P < 0.001 and P < 0.05, respectively). Oxysterols in liver disease, particularly 24(S)-hydroxycholesterol, were greater in urine than serum. Oxysterols change developmentally and might serve as a biomarker for pediatric liver disease. To our knowledge, this is the first such report.

Primary Epidermoid Cyst of Biliary Duct Presenting as Choledochal Cyst.

Choledochal cyst is a cystic dilation of the biliary tree that can increase the risk of malignancy in bile ducts and the gallbladder. These are usually lined by bile duct epithelium, which may undergo intestinal and squamous metaplasia. This is the first report of clinically diagnosed type II choledochal cyst that is entirely lined by metaplastic stratified squamous epithelium, unlike most other cysts, which are histologically lined by bile duct epithelium. This observation can potentially explain the underlying pathogenic mechanism of rare reports of squamous cell carcinomas arising in bile duct systems.

Role of CD56-expressing immature biliary epithelial cells in biliary atresia.

AIM: To analyze the clinical and pathological parameters and expression of the neural cell adhesion molecule (CD56) in patients with biliary atresia (BA). METHODS: Established clinical laboratory markers of hepatic function, including enzyme activity, protein synthesis, and bilirubin metabolism, were evaluated in patients with BA and compared with those in patients with choledochal cysts and neonatal hepatitis. Pathological changes in tissue morphology and fibrosis were examined by histological and tissue collagen staining. Immunohistochemical staining for the biliary epithelial cell markers CD56 and CK19 together with the Notch signaling related molecules Notch1 and Notch2 was performed in the context of alterations in the structure of intrahepatic biliary ducts. RESULTS: Differences in some clinical laboratory parameters among the three diseases examined were observed, but they did not correlate with the pathological classification of fibrosis in BA. Immunohistochemical staining showed the presence of CD56-positive immature bile ducts in most patients (74.5%) with BA but not in patients with choledochal cysts or neonatal hepatitis. The number of CD56-expressing cells correlated with disease severity, with more positive cells present in the later stages of liver damage (81.8% vs 18.2%). Furthermore, bile plugs were mainly found in CD56-positive immature biliary ducts. Notch signaling was a key regulatory pathway in biliary duct formation and played a role in tissue fibrosis. Notch1 was co-expressed in CD56-positive cells, whereas Notch2 was found exclusively in blood vessels in the portal area of patients with BA. CONCLUSION: The maturation of biliary epithelial cells and the expression of Notch may play a role in the pathogenesis of BA.

Serum insulinlike growth factor-I in biliary atresia.

BACKGROUND/PURPOSE: Low level of Insulinlike growth factor-I (IGF-I) has been reported in children with chronic liver disease like biliary atresia (BA) awaiting liver transplantation. However, there has been no report on IGF-I in BA managed without liver transplantation. METHODS: The authors measured IGF-I and growth hormone (GH) in 21 postoperative BA, and 17 choledochal cysts (CC) as a control with normal liver function. To avoid an influence of aging, IGF-I was analyzed after converting them into a newly defined index "IGF%." IGF% is proportional to the lower limit of the value of IGF-I in gender- and age-matched normal control previously reported in literature. RESULTS: IGF% in BA was significantly lower than that in CC. IGF% tended to be lower in Kasai's type III (atresia at the porta hepatis) and higher in the jaundice-free group. IGF% in patients with esophageal varices was significantly lower. The correlation between choline esterase and IGF% was positive and that for TTT and IGF% was negative. CONCLUSIONS: Low level of IGF-I is a characteristic finding in BA, especially in patients without need of liver transplantation. And it may reflect the severity of pathologic changes (ie, hepatic fibrosis and reduced volume of normally functioning liver) in BA liver.

Measurement of serum total bile acid levels in long-term postoperative follow-up of patients with congenital bile-duct dilatation.

Serum total bile acid levels (STBA), a sensitive indicator of cholestasis, were measured during the long-term postoperative period in patients with congenital bile-duct dilatation (CBDD) (choledochal cyst) and the factors contributing to elevation of STBA were analyzed in 44 patients. Their ages at operation ranged from 1 month to 16 years. A STBA level over 12 nmol/ml on two or more measurements during outpatient follow-up was considered abnormal. Patients were classified into three groups: group 1, STBA, 12-50 nmol/ml; group 2, STBA > or = 50 nmol/ml; group N, STBA normal. In 19 patients (43.2%) STBA was normal. Of the 25 patients (56.8%) with elevated STBA, groups 1 and 2 comprised 12 (27.3%) and 13 patients (29.5%), respectively. The mean age in group N was 5.1 +/- 4.2 years, which was higher than in groups 1 (2.6 +/- 2.3) and 2 (2.3 +/- 2.5 years) ( P< 0.05). Preoperative STBA and total bilirubin were higher in group 2 (79.2 +/- 75.1 nmol/ml resp. 5.2 +/- 4.2 mg/dl) than in groups N (20.1 +/- 32.6, 1.3 +/- 1.4) and 1 (22.8 +/- 37.2, 1.4 +/- 1.0) ( P< 0.05). Preoperative alkaline phosphatase and gamma-glutamyl transpeptidase were higher in group 2 (1,006 +/- 872 IU/l, 452 +/- 326 IU/l) than in group N (573 +/- 371, 205 +/- 238) ( P< 0.05). Histologic findings on liver biopsy showed fibrosis in 38.5% of group 2 patients, which was significantly higher than in groups N (15.8%) and 1 (16.7%) ( P< 0.05). Cholestasis was detected in 41.7% of group 1 and 61.5% of group 2 patients, compared to 10.5% of group N patients ( P< 0.05). Postoperative elevation of STBA may thus persist in more than one-half of patients with CBDD, and is likely to occur in patients of young age who have severe cholestasis or liver fibrosis preoperatively. Further investigations may be required in regard to the development of postoperative complications.

Congenital dilatation of the bile duct in 100 instances and its relationship with anomalous junction.

Congenital dilatation of the bile duct (CDBD) or choledochal cyst has been demonstrated to be associated with an anomalous junction of the pancreaticobiliary ductal system. Multifarious clinical signs and symptoms of CDBD have been shown to be closely related with the presence of this anomalous junction. In the present study, 100 instances of CDBD treated surgically at our institutions during a 30 year period were classified into two types according to the morphologic features of dilatation of the bile duct; there were 77 instances of the cystic type and 23 of the cylindric type. Morphologic features of the lesion, clinical signs and symptoms and laboratory findings in these 100 instances were clinically analyzed. In almost all of the patients who were less than one year of age, the disease was of the cystic type and patients presented with either a palpable mass or jaundice as the main symptom. In patients more than one year of age, the disease was of either the cystic or cylindric type. A history of episodes of characteristic abdominal pain accompanied by elevated levels of serum amylase was present in 70 of the patients with the cystic type of disease and in all of the patients with the cylindric type. Histologic sections from the patients showed glandular formation with chronic inflammation, possibly a result of refluxed activated pancreatic juice; in contrast, histologic sections from the remaining patients of all ages showed only thickening of the fibrous layer. Thus, such variable morphologic features and clinical signs and symptoms in CDBD are highly dependent on two factors--the age at onset and the reflux of pancreatic juice into the bile duct through the common channel.