Biliary strictures have been described more frequently in adults than in children. In adults, strictures are found primarily in the common bile duct and are associated with trauma, chronic pancreatitis, recurrent cholangitis, operative injury during cholecystectomy, and neoplasms (1). In children they are generally associated with cholestasis, congenital anomalies of the biliary system, or surgical trauma such as liver transplantation. Intrahepatic biliary strictures have rarely been described. They may occur in association with choledochal cysts (2). However, they have not been convincingly described in association with congenital diseases of the intrahepatic bile ducts, demonstrated histologically by ductal plate malformation (DPM) (3). Ductal plate malformation is caused by the persistence of immature biliary structures secondary to abnormal remodeling of the infantile biliary tree (3). The spectrum of these diseases is broad including congenital hepatic fibrosis (CHF) that involves primarily interlobular bile ducts and is associated with autosomal recessive polycystic kidney disease (ARPKD); Caroli's disease, which affects the large intrahepatic bile ducts; and Caroli's syndrome, which involves bile ducts at all levels, including segmental ducts, and is associated with CHF (3). We describe a child with hepatosplenomegaly without hyperbilirubinemia who had a noninflammatory stricture of the common hepatic duct and a liver specimen with characteristics suggestive of CHF.
The patient was a 4.5-year-old girl in her usual state of good health except for an upper respiratory infection, who appeared mildly icteric, and had hepatosplenomegaly and spider hemangiomas on both cheeks. She had one or two stools a day that were firm and green. There was no hematemesis, hemoptysis, hematochezia, or melena.
She was the appropriate-for-gestational-age, full-term product of a normal pregnancy. There was no history of neonatal jaundice, blood transfusions, drug abuse, or drug allergies. There was no known family history of liver disease or hemoglobinopathy. A maternal grandfather and several paternal family members had had cholecystectomies at 50 to 60 years of age. No relatives had undergone splenectomy.
On physical examination, she was afebrile, and vital signs were normal. The weight was 15.9 kg, which plotted to the 25th percentile, and the height was 98.4 cm, which plotted between the 5th and 10th percentiles. She had mild respiratory distress with scattered wheezes. There was some shotty cervical lymphadenopathy. The liver measured 7 cm below the right costal margin at the midclavicular line with a firm, smooth edge that was nontender. The spleen tip was 7 cm below the left costal margin at the midclavicular line. There were no rashes or palmar erythema. She had a reticulated-pattern angioma on her face.
Initial abdominal ultrasound showed hepatosplenomegaly, a gallbladder with sludge but no stones, and a dilated common bile duct measuring 8 mm (normal, ≤4 mm). There was hepatopedal flow in the portal vessels. Kidneys were normal. Abdominal computed tomographic (CT) scan confirmed that the kidneys were normal.
Hepatocellular enzymes were mildly elevated: aspartate aminotransferase, 140 U/l (normal range, 16-45 U/l), and alanine aminotransferase, 102 U/l (normal range, 3-30 U/l). Biliary injury was suggested by γ-glutamyl transpeptidase, 558 U/l (normal range, 5-55 U/l), and alkaline phosphatase, 529 U/l (normal range, 68-254 U/l). However, bilirubin was normal. Hepatitis A, B, and C and Epstein-Barr viral serologies were negative, and the antismooth muscle antibody was less than 1:20 α1-Antitrypsin phenotype was MS. Sweat test results were normal. Endoscopic retrograde cholangiopancreatography (ECRP) showed a high-grade stricture of the distal common hepatic duct (CHD; Fig. 1). The stricture was short, and there was marked proximal dilatation. The common bile duct and pancreatic duct were both normal.
At surgery, markedly dilated right and left intrahepatic bile ducts were noted. The distal common bile duct appeared normal in caliber. A cholecystectomy and Rouxen-Y right and left hepaticojejunostomy were performed. Liver enzymes normalized within 2 months after surgery. Abdominal ultrasound performed 6 months after surgery showed no residual intrahepatic biliary dilatation.
The wedge liver biopsy performed during surgery showed broad septa of dense fibrous connective tissue surrounding islands of hepatic parenchyma. Antibodies to cytokeratins highlighted the elongated, cystically dilated structures of biliary origin lined by regular cuboidal biliary epithelium (Figs. 2, 3). There was focal mild immunoreactivity in cells at the edge of hepatocyte nodules (Fig. 2). The common hepatic duct showed scarring and luminal stenosis (Fig. 4).
The findings of biliary dilatation on abdominal ultrasound were unexpected. The differential diagnosis of hepatosplenomegaly with dilated bile ducts is limited. Infection, congenital cystic liver diseases such as Caroli's disease, spontaneous perforation of the bile duct, a forme fruste of biliary atresia, a variant of a choledochal cyst, cystic fibrosis, and gallstones were all considered. A normal result in a sweat chloride test made cystic fibrosis unlikely. The other diseases were improbable based on clinical, ultrasonographic, and cholangiographic evaluations.
The ERCP confirmed a stricture of the CHD. The liver specimen showed evidence of abnormal remodeling of the biliary plate in the spectrum of Caroli's syndrome and CHF. The fibrous septa contained primarily congenitally abnormal plates characterized by cystic dilatation of the bile ducts, rather than newly proliferating bile ducts.
Desmet suggested that defects of ductal plate remodeling contribute to the development of congenital cystic diseases of the bile duct (3). The child described in this report had histologic evidence of CHF in conjunction with a CHD stricture. The association of DPM with biliary strictures has been suggested but not clearly described (4). The phenotype of DPM depends, in part, on the stage at which biliary plate remodeling is arrested. On one end of the spectrum are the diseases characterized by involution of the biliary tree, such as biliary atresia (3). When DPMs are noted, an in utero onset of biliary atresia is inferred. Specimens obtained in follow-up liver biopsies in children with the initial histologic picture of both biliary atresia and DPM reveal CHF-like changes (3). It has been suggested that the histologic lesion represents continuing mild, destructive cholangitis. On the opposite end of the spectrum from the diseases characterized primarily by involution of the bile ducts are the fibrocystic diseases, such as Caroli's disease, which is characterized by ectasia of the intrahepatic biliary structures. Caroli's disease represents nonobstructive dilatation of the large intrahepatic bile ducts. There appears to be an arrest of remodeling in an early stage of embryogenesis that alters the structure of the main intrahepatic bile ducts, but not the more peripheral interlobular bile ducts (3). Caroli's syndrome combines components of destructive cholangitis and ectasia. It is CHF in association with Caroli's disease. In CHF, portal tracts contain dilated ductal plate remnants alone or buried within connective tissue bands. In Caroli's syndrome, the biliary injury exerts its effect during a more prolonged period, affecting both the main hepatic ducts and the peripheral interlobular ductules.
Chapoy et al. (4) described a 3-year-old child with hepatosplenomegaly without pruritus or jaundice who had a CHD stricture that was unassociated with hepatic inflammation. Unlike our patient, the primary histologic feature was bile duct proliferation with fibrosis. No DPM was described. The child had not had previous biliary surgery. Additionally, because the stricture was located in the CHD, where congenital strictures are most common, it was thought to be congenital. Because there was no evidence of immature biliary structures histologically and the child's liver inflammatory indices improved after surgery, it was thought that she did not have CHF. Kumar et al. (1) reported a 6-year-old anicteric child with a 2-year history of intractable pruritus secondary to a stricture at the junction of the right and left intrahepatic bile ducts. The gallbladder showed transmural fibrosis. A liver specimen showed mixed inflammatory infiltrate, bile duct proliferation, and fibrosis. No DPM was appreciated. The cause of the stricture was postulated to be congenital or inflammatory (1). Takabe et al. (5) described a 9-year-old child with jaundice and anorexia without pruritus. On the basis of elevated tumor markers, cholangiocarcinoma was suspected, but no tumor was found. At laparotomy, the CHD and left hepatic duct were cordlike. The CHD wall was fibrotic and thickened but showed minimal inflammation. However, the liver specimen was described as normal. Takabe et al. suggested a new entity, which they termed "segmental pericholangial fibrosis."
In this child, we postulate that the CHD stricture was secondary to an in utero insult that altered the development of the biliary ductal system (6). Histologically, this case presented features of CHF. However, clinically, the patient did not have the more common features of CHF (cholangitis or complications of cirrhosis), and she had no associated renal disease. The macroscopic dilatation of the biliary tree described in this child is uncommon in patients with CHF, except in association with nonobstructive dilatation of the hepatobiliary tree (Caroli's disease). After surgery, she appeared to have decompression of the intrahepatic bile ducts, regression of splenomegaly, and improvement of hepatic inflammatory indices. Therefore, the clinical appearance of her condition did not indicate CHF.
Another consideration is whether she could have had a forme fruste of biliary atresia with incomplete destruction of the extrahepatic biliary system as an infant and continued mild destructive cholangitis, as described by Desmet in some children with biliary atresia (3,6). The significance of the α1-antitrypsin MS phenotype in this child's illness is negligible. No periodic acid-Schiff-positive, diastase-negative globules were found. α1-Antitrypsin deficiency has not been described in association with DPM (7,8). This child will continue to be observed prospectively for complications of cirrhosis. This case reinforces the importance of considering disease of the biliary tree, even in the presence of a normal bilirubin.
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