Agenesis of the gallbladder without extrahepatic biliary atresia

Agenesis of the gallbladder without extrahepatic biliary atresia is a rare disorder. At the UCLA-affiliated hospitals, 12 patients were classified in the following groups: (1) multiple fetal anomaly, (2) asymptomatic, and (3) symptomatic. All four patients in the multiple fetal anomaly group died of their other congenital defects. In the three patients in the asymptomatic group, the absent gallbladder was an incidental finding at autopsy. The five patients in the symptomatic group underwent operations for symptoms suggestive of biliary tract disease, with no gallbladder found; all were symptom free postoperatively. Operative strategy should include a complete exploration, operative cholangiography, and common bile duct exploration as necessary. Possible mechanisms responsible for symptoms include primary duct stones, biliary dyskinesia, or nonbiliary disorders. Computed tomography, biliary manometry, upper gastrointestinal tract endoscopy, and endoscopic cholangiography (with or without sphincterotomy) could be employed if symptoms continue.     

Biliary web--a rare cause of extrahepatic biliary obstruction

A case of an isolated mucosal web of the common hepatic duct is presented. Such extrahepatic biliary webs are extremely rare causes of biliary obstruction, likely congenital in nature, but presenting in later life due to the initial patency of these webs in allowing bile drainage from the liver. The relevant literature is reviewed; diagnostic and therapeutic aspects are discussed.     

Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia.

BACKGROUND: Progressive destruction of intrahepatic bile ducts may determine outcome in extrahepatic biliary atresia (EHBA) despite successful portoenterostomy. The aim of this study was to characterize the inflammatory infiltrate of a large series of cases of biliary atresia and relate these findings to clinical outcome. METHODS: Immunohistochemical analysis was performed on frozen tissue sections of extrahepatic biliary tree and liver biopsies obtained (August 1996 to March 1998) from 28 infants with EHBA and 8 liver biopsy specimens from age-matched controls with other cholestatic liver disorders. A semiquantitative scoring system was designed to evaluate the staining with a panel of antibodies to the CD4, CD8, CD25, CD56, CD68, CD71 antigens and to HLA-DR, ICAM-1, VCAM-1, E-selectin and LFA-1. The infants then underwent followup prospectively and divided into 2 prognostic groups at 12 months postoperatively: those who had cleared their jaundice (graded as a good outcome [n = 19]), and those who required liver transplantation or who had failed to clear their jaundice (defined as > 50 micromol/L; graded as poor outcome [n = 9]). RESULTS: CD4(+) lymphocytes and CD56(+) (NK cells) predominated in the liver of infants with EHBA as compared with controls. The infiltrating cells exhibited marked proliferation (CD71 expression) and activation (particularly LFA-1 but also CD25 expression). A smaller subpopulation of the cells also expressed VCAM and E-selectin. HLA-DR was strongly expressed on Kupffer cells and to a lesser extent on proliferating bile ducts and sinusoidal endothelium. Expression of the majority of markers was lower in the remnant bile duct tissue than in the liver of EHBA (P <.05) with only HLA-DR and LFA-1 (on infiltrating cells) and ICAM (on endothelium) expressed strongly in the remnant bile duct tissue. Although quantitatively less pronounced, all of these immunohistochemical features also were noted in non-EHBA cholestatic liver tissue. A good outcome at 12 months was associated with lower CD68 (macrophage) expression in both the liver (P <.05) and biliary tree (P <.05) and with reduced expression of ICAM-1 (P =.05) on infiltrating cells in the biliary remnant. CONCLUSIONS: Immunohistochemical patterns of immune-mediated liver injury and inflammation were prevalent features at the time of portoenterostomy. They were neither exclusive to nor characteristic of EHBA. A reduction in the expression of the macrophage marker (CD68) within the liver and biliary remnants and reduction of ICAM-1 expression on infiltrating cells in the biliary remnants appear to be associated with a better postoperative prognosis.     

Biliary atresia: early determination of prognosis

Analyses of bile bilirubin during the first month after Kasai operations, and of the liver biopsies obtained at the time of initial surgery, were done in 67 patients with biliary atresia. Bilirubin excretion (milligrams per day) was determined as the product of the bile volume and its concentration. Operative liver biopsies were evaluated for fibrosis, bile duct proliferation, bile stasis, giant cell transformation, and parenchymal degeneration; the severity of each abnormality was graded on a scale of 0 to 4. A forward stepwise regression procedure using the Cox proportional hazards model identified the relationship between survival and covariants. Thirty-nine of 67 patients died. Of these, 38 excreted less than 6 mg of bilirubin per day during the first postoperative month. The other patient died of a coexisting anomaly. Nine other patients who excreted less than 6 mg of bilirubin per day are alive but are either jaundiced or awaiting transplantation. Nineteen patients who excreted greater than or equal to 6 mg of bilirubin per day are alive (mean follow-up, 61 months) with normal or near-normal liver function. The severity of liver fibrosis, bile duct proliferation, and bile stasis did not correlate with survival, whereas giant cell transformation and parenchymal degeneration were highly significant (P less than or equal to .000 and P less than or equal to .0003, respectively). Twenty-six infants with grade 1-4 giant cell transformation or grade 2-4 parenchymal degeneration had a mean survival of 11 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rotavirus particles in the extrahepatic bile duct in experimental biliary atresia

Background

Biliary atresia (BA) is the most common indication for liver transplantation in children. The experimental model of BA, induced by rotavirus infection in neonatal mice, has been widely used to investigate the inflammatory aspects of this disease. We investigated the kinetics and the localization of the viral infection in this murine model.

Methods

In this study 399 animals were employed for a detailed investigation of rhesus rotavirus (RRV)-induced BA. RRV kinetics was analyzed by rtPCR and its (sub) cellular localization investigated using whole mounts which were further processed for confocal and electron microscopy.

Results

The BA mouse model resulted in up to 100% induction of atresia following RRV injection. The kinetics of RRV infection differed between liver and extrahepatic bile ducts. While the virus peak up to day 10 postinfection was similar in both organs, the virus remained detectable in extrahepatic bile duct cells up to day 21. Interestingly, RRV particles were localized not only in cholangiocytes but also in cells of the subepithelial layers, potentially macrophages.

Conclusions

RRV remains present in the extrahepatic bile duct cells after an initial virus peak. Viral particles were detected in subepithelial cells in contrast to the described tropism toward cholangiocytes.     

Histopathologic study of the extrahepatic biliary system in uncorrectable congenital biliary atresia: its pathogenesis and type of atresia

Histopathologic study was carried out on specimen of extrahepatic biliary system in 23 patients with congenital biliary atresia, and the data were compared with those obtained from a control group of 43 autopsy cases of newborns and infants. In the control cases, accessory tubulo-alveolar glands were observed around the extrahepatic bile duct, and in addition some small ductules were observed in the area of the porta hepatis. In cases of biliary atresia, characteristic findings were histologically detected at each level of the extrahepatic biliary system. In the area of the porta hepatis, there were many epithelial luminal structures in fibrous tissue with inflammatory infiltrates. Near the confluence, the bile duct completely disappeared to be replaced by fibrosis, and in the area between the porta hepatis and the confluence, granulation tissue surrounded by fibrosis was observed. The epithelial luminal structures in the area of the porta hepatis were thought to originate from the bile duct, draining ductules and accessory glands observed in the normal controls. These structures tended to decrease in number with time. In cases possessing a patent common bile duct, the gallbladder showed many mucous glands and no inflammatory changes. On the other hand, in cases with an obliterated common bile duct, the gallbladder showed chronic atrophic cholecystitis without any mucous glands. The pathogenesis remains unknown, but it is thought that this disorder results from non-infectious inflammatory changes initiated near the confluence of the normally developed bile duct.     

Resting energy expenditure is increased in infants and children with extrahepatic biliary atresia

To determine if liver dysfunction in children affects energy and macronutrient homeostasis, we performed 13 metabolic studies in 11 patients (age, 17.8 +/- 5.9 months [mean +/- SEM]) with extrahepatic biliary atresia (EHBA). Nutritional balance, indirect calorimetry, anthropometry, and biochemical liver function tests were utilised. Sixty-four percent of the energy losses were in the form of stool fat. Energy expenditure (68 kcal/kg/d) was 29% higher than normal (P less than 0.0025). Only one third of the metabolisable energy intake (37 kcal/kg/d) was stored in the body for new tissue synthesis. In spite of the bountiful protein intake for age, the increased protein oxidation (2g/kg/d) resulted in a virtually zero mean nitrogen balance. In addition, four patients oxidised endogenous protein as well. The respiratory quotient was 0.96, and did not change significantly between pre- and post-meal measurements, suggesting a predominant utilisation of carbohydrate for energy metabolism. Net lipid oxidation was severely diminished. We found that the higher the serum aspartate aminotransferase level (previously named SGOT), the lower the net fat oxidation, and the higher the conversion of glucose to fat. These data suggest that markedly increased energy expenditure contributes to the malnutrition of patients with EHBA. We characterised for the first time how severe liver disease in infants and children affects carbohydrate, fat, and protein metabolism, thus inducing protein-energy malnutrition.     

Review of historical cohort: ursodeoxycholic acid in extrahepatic biliary atresia

Background

Ursodeoxycholic acid is a bile acid that was found to increase bile flow, protect hepatocytes, and dissolve gallstones.

Purpose

The objective of this study is to review ursodeoxycholic acid in infants and children with extrahepatic biliary atresia.

Methods

We used a statistical analysis of data of records of infants and children having extrahepatic biliary atresia who underwent Kasai portoenterostomy and attended Hepatology Clinic, New Children's Hospital, Cairo University, Egypt, from May 1985 until June 2005.

Results

Of 141 infants with extrahepatic biliary atresia, 108 received ursodeoxycholic acid for mean duration ± SD of 252.6 ± 544.9 days in a dosage of 20 mg/kg per day. The outcome of infants who did not receive ursodeoxycholic acid and those who did was the following: 8 (24.2%) and 11 (10.18%) had a successful outcome (P = .043), 0 (0%) and 7 (6.4%) improved (P = .148), 25 (75.7%) and 84 (77.7%) had a failed outcome (P = .489), and none vs 5 died (4.6%) (P = .135), respectively. The predictors of successful outcomes were age less than 65 days at portoenterostomy (P = .008) and absence of ursodeoxycholic acid intake (P = .04) with a likelihood of a successful outcome that was 2.8, that associated with ursodeoxycholic acid intake.

Conclusion

In this cohort of infants with extrahepatic biliary atresia, ursodeoxycholic acid was not shown to be effective, and its use was associated with a plethora of hepatic and extrahepatic complications.     

Hepatic infarction and acute liver failure in children with extrahepatic biliary atresia and cirrhosis

Acute hepatic failure developed in four patients (aged 7 to 13 months) who had extrahepatic biliary atresia treated initially by portoenterostomy. Two were stable outpatients with minimal jaundice, while the other two were hospitalized for metabolic or nutritional complications. Postmortem examination in each patient revealed massive acute hepatic infarction with few surviving hepatocytes. In all cases, the hepatic failure had been preceded by an episode of hypotension and/or hypovolemia. The exact pathogenesis of the infarction remains unclear but it may be related to decreased hepatic blood flow secondary to biliary obstruction. The only effective treatment for these patients is intensive supportive care and urgent liver transplantation.     

Neuroendocrine differentiation and prognosis of extrahepatic biliary tract carcinomas.

From 1980 to 1987, 35 patients underwent exploratory surgery for carcinomas of the extrahepatic biliary tract (EBT). Samples from 28 of these tumors (15 gallbladder, 13 bile duct) were assessed by immunohistochemical analysis for exocrine and/or neuroendocrine differentiation. Seven patients were excluded from the study because of insufficient available specimen or loss to follow-up. Paraffin sections were immunostained for neuroendocrine differentiation markers: neuron-specific enolase (NSE), chromogranin-A, synaptophysin, serotonin, somatostatin, substance-P, and glucagon. Additional sections were also stained with monoclonal antibody A-80 that recognizes a glycoprotein related to exocrine differentiation. The tumors were reclassified on the basis of immunophenotyping data: (I) pure exocrine carcinoma (n = 8); (II) predominantly exocrine carcinoma with occasional neuroendocrine cells (n = 9); (III) mixed exocrine-neuroendocrine carcinoma (n = 4); (IV) pure neuroendocrine (n = 2); and (V) predominantly neuroendocrine with occasional exocrine cells (n = 5). Survival time among the two pure neuroendocrine (group IV) and five predominantly neuroendocrine carcinomas (group V) was significantly less than the survival time of patients from the other groups (2.6 +/- 2.2 months vs 13.5 +/- 12.3 months; p = 0.015). No difference was noted between groups in extent of disease, treatment rendered, or location of tumor (bile duct vs gallbladder). This study indicates that (1) the incidence of neuroendocrine differentiation in cancers of the EBT is higher than generally recognized, (2) carcinomas of the EBT may be phenotypically reclassified on the basis of immunohistochemical analysis, and (3) the presence of pure or predominant neuroendocrine differentiation in carcinomas of the EBT is associated with shorter survival time than carcinomas with pure or predominant exocrine differentiation (or mixed exocrine and neuroendocrine factors).     

A histopathological study of the remnant of extrahepatic bile duct in so-called uncorrectable biliary atresia

Histopathological study of the remnant of extrahepatic bile ducts in 40 cases of so-called uncorrectable biliary atresia, upon which we operated the last three years, has been performed. The histological findings of the remnant were classified into three types.Only two cases were found to have type 1a ducts in the porta hepatis area, from which we can expect better prognosis postoperatively. We also found that as the patients become older, the size of the duct in the remnant becomes smaller and the hepatic fibrosis becomes more remarkable. Therefore the operation should be performed in the infant with this lesion as young as possible.As for the evaluation of operative results of hepatic portoenterostomy for this lesion, a proper evaluation can be made only in those cases in which a microscopic examination of the remnant of extrahepatic bile duct at the porta hepatis area has been adequately performed.Concerning the pathogenesis of biliary atresia, we presume that congenital abnormalities of bile ducts are a basic factor, and additional nonspecific inflammation and bile stasis complete its pathological condition.     

Biliary atresia in the newborn

A prenatal sonographic diagnosis of extrahepatic biliary atresia was made and, 76 hours after birth, operatively confirmed. A standard Kasai operation was performed, with the exception of the use of an ancillary appendiceal conduit to provide biliary drainage of an independent bile duct draining the right anterior hepatic segment. Hepatic and ductal histology were identical to those usually found in biliary atresia in a 6- to 8-week-old infant. The child is well at 16 months.     

The extent of biliary proliferation in liver biopsies from patients with biliary atresia at portoenterostomy is associated with the postoperative prognosis

Background/Purpose

In biliary atresia (BA), a derangement in the biliary system remains, despite portoenterostomy performance. Many factors can influence the disease progression rate. This study aimed to analyze the association between biliary proliferation extent in biopsies from BA patients and postoperative prognosis.

Methods

Biliary proliferation was evaluated by a morphometric analysis of the cytokeratin 7 positivity percentage (PCK7) in wedge liver biopsies from 47 BA patients. The extent of fibrosis was evaluated by a fibrosis score (FS). The outcome 1-year native liver survival was correlated, using a multivariable regression analysis, with PCK7, FS, and age at portoenterostomy.

Results

The PCK7 ranged between 0.80% and 14.79% (M ± SD = 7.36% ± 4.15%). Patients who died or underwent transplantation had higher PCK7 than survivors with their native livers (P < .001). The area under the receiver operating characteristic curve for PCK7 in relation to the outcome was 0.845 (P < .001). The cutoff point of PCK7 for the maximal effect on postoperative prognosis was 10.18% (sensitivity = 0.71, specificity = 0.88). The PCK7 was the only studied variable associated with 1-year native liver survival, independently of age and FS (P = .002).

Conclusion

The extent of biliary proliferation at portoenterostomy, evaluated by PCK7, was associated with 1-year native liver survival of BA patients.     

Effects of postoperative cholestyramine and phenobarbital administration on bile flow restoration in infants with extrahepatic biliary atresia

Surgical restoration of bile flow in patients with extrahepatic biliary atresia (EHBA) results in the disappearance of clinical cholestasis in about 30% of cases. It is suggested that early postoperative administration of phenobarbital (PB) or cholestyramine (Ch) may improve this percentage. Eighty patients were randomly divided into three subgroups comprising 27 who were treated with Ch (4 g/d), 27 who were given PB (7.5 to 10 mg/kg/d) during the first 3 postoperative months and 26 untreated patients, who served as controls. Cholestasis was observed to disappear in 38 (group I) patients and to persist in 42 (group II) patients, as judged from their total blood bilirubin levels, the conjugated/total bilirubin ratio, measurements of cholesterol, bile acids and alkaline phosphatase, and of Rose Bengal fecal excretion. Neither Ch nor PB significantly improved the degree or duration of cholestasis in either group.