Renal abnormalities in paucity of interlobular bile ducts

Paucity of interlobular bile ducts is a common histologic characteristic in persistent conjugated hyperbilirubinemia of infancy. It occurs in two forms: the syndromatic and the nonsyndromatic types. The syndromatic form is also called arteriohepatic dysplasia. The nonsyndromatic type of paucity of interlobular bile ducts occurs less frequently and is usually associated with more severe disease and a less favorable prognosis. We present two unusual renal anomalies in association with paucity of interlobular bile ducts. In the first case, juvenile nephronophthisis was diagnosed in a 4-week-old infant with arteriohepatic dysplasia; the patient died from severe renal disease by 2 months of age. The second case presented with severe bilateral hydronephrosis and hydroureter secondary to posterior urethral valves associated with the nonsyndromatic form of paucity of interlobular bile ducts. He, however, improved after corrective surgery of the urethral valves. Other renal abnormalities previously reported in the literature in association with chronic liver disease are also reviewed.     

Nonsyndromic paucity of interlobular bile ducts: report of 10 patients

OBJECTIVES: Only a few reports of nonsyndromic paucity of interlobular bile ducts (NS-PILBD) have been published. The authors' aim was to outline the clinical and laboratory profile of patients with NS-PILBD diagnosed at a tertiary referral center. METHODS: The authors reviewed all the reports of pediatric liver biopsies performed between 1991 and 2000 at their institution. Upon diagnosis of NS-PILBD, patients' records were examined for clinical, laboratory, and histologic data, and liver biopsy specimens were re-evaluated. RESULTS: Three hundred biopsies were performed in children during the study period, of which 64 were in infants younger than 1 year. NS-PILBD was diagnosed in 10 of 64 (16%) biopsy specimens. Mean age at presentation was 10 days (range, 1 day-6 weeks), and mean follow-up was 4.5 years (range, 1-9 years). An underlying condition was identified in 70% of children with NS-PILBD: namely congenital cytomegalovirus (n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), mitochondrial DNA depletion (n = 1), Niemann-Pick type C (n = 1), and arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC syndrome; n = 1). All children presented with jaundice. Four children had initially acholic stools. At their last follow-up visit, failure to thrive was present in five children, and cholestasis in six children. Mortality was noted only in children with metabolic diseases (n = 2). CONCLUSIONS: In the study, NS-PILBD was common in young children undergoing liver biopsy. Although NS-PILBD is nonspecific, a wide survey for inborn errors of metabolism should be included in the diagnostic work-up of NS-PILBD. In the authors' center, the association of certain metabolic diseases with NS-PILBD carries a grave prognosis.     

Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts

Severe failure to thrive is an important feature in children with both syndromic and nonsyndromic paucity of interlobular bile ducts (PILBD). Thirteen children age 7 months-11 years with PILBD had pancreatic secretions in duodenal aspirate measured for 40 min after secretin-pancreozymin stimulation, six of these children had chronic diarrhoea. Studies were also performed in seven children age 2-12 years who presented with failure to thrive or nonspecific diarrhoea that subsequently resolved. The results of the control and the PILBD children were similar except in the six with chronic diarrhoea. These children had significant reductions in total volume of duodenal aspirate (p less than 0.05), bicarbonate concentration (p less than 0.02) and output (p less than 0.05), and in lipase concentrations (p less than 0.005). Five of these children have had a reduction in stool frequency and more rapid weight gain since receiving pancreatic supplementation. In children with PILBD and diarrhoea, pancreatic insufficiency may be a contributory factor to poor weight gain. These children may benefit from pancreatic extract supplementation.     

SZ phenotype alpha-1-antitrypsin deficiency with paucity of the interlobular bile ducts

Abstract A child is reported whose alpha-1 -antitrypsin phenotype is SZ and who has chronic cholestatic liver disease that began in the neonatal period. Liver biopsy demonstrated paucity of the interlobular bile ducts, marked hepatocellular deposition in periportal areas of PAS-positive, diastase-resistant granules, and bridging portal fibrosis. The association of paucity of the interlobular bile ducts with SZ phenotype alpha-1-antitrypsin deficiency has not been reported previously.     

SZ phenotype alpha-1-antitrypsin deficiency with paucity of the interlobular bile ducts

A child is reported whose alpha-1-antitrypsin phenotype is SZ and who has chronic cholestatic liver disease that began in the neonatal period. Liver biopsy demonstrated paucity of the interlobular bile ducts, marked hepatocellular deposition in periportal areas of PAS-positive, diastase-resistant granules, and bridging portal fibrosis. The association of paucity of the interlobular bile ducts with SZ phenotype alpha-1-antitrypsin deficiency has not been reported previously.     

Neonatal hepatitis syndrome with paucity of interlobular bile ducts in cystic fibrosis.

A male infant presenting with neonatal hepatitis syndrome, characterized by conjugated hyperbilirubinemia and very mild liver function test abnormalities, at 2 weeks of age was found to have no excretion of radioisotope into the intestinal tract on hepatobiliary scan. Liver biopsy revealed severe interlobular bile duct paucity. Other features of Alagille's syndrome were not present; other conditions frequently associated with interlobular bile duct paucity were also excluded. Subsequently, the infant was found to have cystic fibrosis. Cystic fibrosis is thus another disease that may be associated with paucity of interlobular bile ducts presenting as neonatal hepatitis syndrome, and this represents a different pathogenesis of cholestatic jaundice in neonates with cystic fibrosis besides those previously recognized.     

Peripheral neuropathy and chronic cholestasis due to paucity of interlobular bile ducts (author's transl)

Peripheral neuropathy was observed in three patients in the course of a chronic cholestasis due to paucity of interlobular bile ducts associated with several malformations (Alagille's syndrome). In two patients, investigations showed a chronic axonal neuropathy. In a third, the low density of myelinated fibers was associated with onion-bulb proliferation on the Schwann-cells and myelin abnormalities related to an associated dominant inherited primary hypertrophic neuropathy. The responsibility of a chronic vitamin E deficiency in the development of axonal lesions is discussed.     

Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases

We have observed two types of paucity of interlobular bile ducts (PILBD) in children with chronic cholestasis: the syndromic type, which is more frequent (80 cases), and the nonsyndromic type (31 cases). Study of patients with syndromic PILBD has enabled us to recognize five major features: peculiar facies (95%), chronic cholestasis (91%), posterior embryotoxon (88%), butterfly-like vertebral arch defects (87%), and peripheral pulmonary artery hypoplasia or stenosis, either isolated or associated with complex cardiovascular abnormalities (85%). By observing these major features, it is possible to differentiate the "complete" syndrome, in which all five features are present (26 cases), from the "partial" syndrome, in which only four (42 cases) or three (12 cases) major features are present. Other less frequent features were observed in patients with complete or partial syndrome: growth retardation (50%), mental retardation (16%), renal disturbances, other vascular malformations, bone abnormalities, high-pitched voice, and delayed puberty. Death occurred in 21 (26%) patients with syndromic PILBD. Therapy consisted of supplementation of medium-chain triglycerides and fat-soluble vitamins and administration of cholestyramine or phenobarbital. An autosomal dominant mode of transmission, with variable penetrance, seems likely.     

Syndromic paucity of the intrahepatic bile ducts: diagnostic difficulty; severe morbidity throughout early childhood

The clinical, biochemical, and histological features of 27 children with syndromic paucity of the interlobular bile ducts are described. All presented in the first 5 months of life, 21 with jaundice, two with spontaneous bleeding due to vitamin K malabsorption in addition to jaundice, two with pruritus, and two with failure to thrive. Interlobular bile ducts were abundant in liver biopsies from five (18% of cases) in the first 6 months of life. The degree of portal fibrosis and cellular infiltrate was mild in all except three patients. Clinically significant heart lesions occurred in 52% but only 22% had peripheral pulmonary stenosis. Characteristic facial appearances were present in only 70%; embryotoxon and vertebral anomalies were present in 56 and 33%, respectively. Two infants died of cardiovascular complications, one of alimentary bleeding and one of progressive liver disease. Complications of vitamin K deficiency occurred in 15%, vitamin D deficiency in 30%, and vitamin E deficiency in 37%. Survivors at ages of 19 months to 16.5 years had considerable morbidity with pruritus occurring in 70%, jaundice in 48%, xanthomas in 30%, 74% having hepatomegaly and 63% splenomegaly. All had abnormal biochemical tests of liver function, 90% had growth retardation, and 50% developmental delay. We conclude that differentiation from extrahepatic biliary atresia can be difficult if biliary flow cannot be demonstrated. Prevention of fat-soluble vitamin deficiency is essential. Further research is required to decrease the morbidity associated with this syndrome in infancy.     

Alagille syndrome with a spontaneous appearance of the interlobular bile ducts

We report a rare case of a 10 year old girl diagnosed as having Alagille syndrome on the basis of a characteristic face, posterior embryotoxon, cholestasis, peripheral pulmonary artery stenosis and the absence of interlobular bile ducts in a liver biopsy at 1.5 years of age. Since 1.5 years old, she had been in good health without medication and the serum biochemical liver function tests indicated no progression of cholestasis. A second liver biopsy at 9.5 years of age showed normal interlobular bile ducts confirmed by anti-keratin staining at each of the five examined portal areas. Alagille syndrome is usually associated with the progressive disappearance of interlobular bile ducts. The findings of interlobular bile ducts in the second liver biopsy were therefore rare and unique to this case.     

Spontaneous perforation of the bile ducts

Spontaneous perforation of the extra-hepatic bile ducts in infancy is rare and of unknown etiology. Its finding at laparotomy in a 2 month-old premature with artificial ventilation allows to underline that the diagnosis may be difficult and may necessitate ultrasonography and even hepatobiliary scintigraphy.