Biliary atresia (BA) is a neonatal disease of unknown origin, characterised by an obstruction of the bile ducts (1). Patients with BA present with neonatal cholestatic jaundice. If untreated, BA leads to biliary cirrhosis in the first months of life and death within the first years. Current treatment of BA is sequential (2,3): In the neonatal period, the Kasai operation (hepatoportoenterostomy) consists in the resection of the extrahepatic biliary tree and anastomosis of a jejunal en-Y loop to the liver hilum (porta hepatis) (4). Technical variants, such as hepatoportocholecystostomy, may be performed according to the anatomy of the extrahepatic biliary remnant. The Kasai operation restores some biliary flow in approximately half the cases and allows survival with the native liver of approximately one third of the patients at 10 years (5) and one fourth to one fifth at 20 years (6). Secondary liver transplantation (LT) may be needed, usually in the first years of life, if the Kasai operation fails to restore the biliary flow and/or if complications of biliary cirrhosis occur. With this sequential treatment, overall BA patients survival rate is approximately 90% at the present time (7).
Several prognostic factors of median-term success of the Kasai operation have been identified: anatomy of the extrahepatic biliary remnant, existence of a polysplenia syndrome, age at Kasai operation and experience of the hospital centre in the management of BA patients (8–12). Liver fibrosis at Kasai operation has also been shown to be linked to a worse restoration of biliary flow and subsequent survival with native liver (SNL) (13–18). However, the relation between portal pressure or liver fibrosis at Kasai operation and the progression to threatening portal hypertension (PHT) is only documented by scarce and conflicting reports (19,20).
By using a very simple index of portal pressure measured during the Kasai operation, we examined the prognostic value of the initial portal pressure, focusing on the median term success of Kasai operation, and the risk for the child of developing significant PHT.
PATIENTS AND METHODS
All 127 patients with BA, born between January 1991 and December 1996, who underwent a Kasai operation or any of its technical variants in Bicêtre University Hospital were prospectively studied. In all cases, the diagnosis of BA was confirmed by operative findings and the histology of the extrahepatic biliary remnant. During the Kasai operation, the umbilical vein was catheterised, and a portal pressure index (PPI), defined by the height of the physiologic saline column above the upper liver surface level, was measured. Sometimes, the umbilical vein was partly stenosed, and calibration with a fine and nontraumatic dilator was necessary before inserting the umbilical catheter. Measurements of the PPI were always repeated once or twice to check if the findings were reproducible.
A surgical liver biopsy was performed, except in 3 patients who underwent a needle biopsy. All liver biopsy specimens were fixed in a formalin-alcohol-acetic acid or Carnoy solution and embedded in paraffin wax. Four-micrometer-thick sections were stained with hematoxylin-eosin-saffron and Masson trichrome. Liver fibrosis was evaluated semiquantitatively according to the METAVIR (fibrosis staged on a 0–4 scale) (21) and Chevallier (fibrosis staged on a 0–35 scale) (22) scoring systems. The fibrosis was assessed independently by a single senior pathologist, expert in pediatric liver diseases (Monique Fabre), blinded to the results of PPI. Median area of liver biopsies was 15 mm2 (range, 3–48); median number of portal tracts observed per biopsy was 22 (range, 9–40).
In the follow-up, upper gastrointestinal endoscopy was performed when clinical and/or echographical signs of PHT were detected. Criteria for significant PHT were defined as follows: digestive bleeding due to PHT and/or presence of esophageal varices ≥grade 2 and/or presence of gastric varices.
The following survival rates were studied: (1) overall patient survival (OS), which starts at birth and ends at death; (2) SNL, which starts at birth and ends at LT or death in nontransplanted patients; (3) in the patients living with their native liver, survival without significant PHT (SwsPHT), which starts at birth and ends when significant PHT appears; and (4) in transplanted patients, posttransplantation survival, which starts at LT and ends at death. Median follow-up was 9 years (range, 0.6–12.5).
The relation between outcome and potential prognostic factors, such as age at Kasai operation, anatomical pattern of the extrahepatic biliary remnant, polysplenia syndrome, PPI, severity of liver fibrosis, type of surgery and postoperative normalization of bilirubin (≤20 μmol/L), were studied. The anatomical pattern of the extrahepatic biliary remnant was determined by operative findings and by preoperative or intraoperative cholangiogram if needed. Complete extrahepatic atresia is defined by obstruction of all the extrahepatic biliary remnant. Partial extrahepatic atresia includes the following patterns: atresia limited to common bile duct, atresia with cyst in the liver hilum communicating with dystrophic intrahepatic ducts, hepatic duct atresia with patency of gallbladder and cystic duct and common bile duct. Polysplenia syndrome (present in 12 patients) includes multiple spleens, associated or not with various malformations such as median liver, preduodenal portal vein, absence of retro hepatic inferior vena cava (with azygos continuation of the inferior vena cava), intestinal malrotation, situs inversus and cardiac malformation(s). Types of surgery included hepatoportoenterostomy (98), hepatoportocholecystostomy (23) and kysto-enterostomy (1).
Survival rates were calculated according to the Kaplan-Meier method. Univariate and multivariate analyses used the log-rank test and the Cox model. All tests were 2-tailed, and differences were considered to be significant for P ≤ 0.05.
Median age at Kasai operation was 55 days (range, 8–116). Measurement of PPI was successful in 113/127 patients (89%) without any complications.
Median PPI at Kasai operation was 15 cm (range, 5–35). There was a positive correlation between age at surgery and PPI (Fig. 1). The METAVIR score of liver fibrosis was 1, 2, 3 and 4 in 27, 37, 41 and 20 patients, respectively. The median Chevallier's score of liver fibrosis was 8 (range, 1–25). Portal pressure index was positively correlated to both scores of fibrosis: Mean (±standard deviation) PPI was 12.8 cm (±4.6), 14.9 cm (±3.6), 16.6 cm (±5.0) and 22.6 cm (±6.4) in patients with METAVIR scores 1 to 4 (P < 0.001), and 13.8 cm (±4.0) and 19.0 cm (±6.2) in patients with Chevallier's scores ≤8 or >8 (P < 0.001).
Five- and 10-year patient survival was 79.1% (standard error [SE] ± 3.7%, at risk at 5 y [AR5y] = 94) and 78.2% (SE ± 3.7%, AR10y = 31), respectively. Five- and 10-year SNL was 41.2% (SE ± 4.4%, AR5y = 50) and 35.7% (SE ± 4.4%, AR10y = 11), respectively. Twelve out of 127 patients (9.4%) died without LT. Five- and 10-year posttransplantation survival was 76.7% (SE ± 5.3%, AR5y = 40) and 76.7% (SE ± 6.8%, AR10y = 6), respectively.
In the univariate analysis, 3 factors were significantly associated with a worse SNL: complete atresia of the extrahepatic biliary remnant, existence of a polysplenia syndrome and PPI >15 cm. Although SNL decreased when the severity of liver fibrosis increased, no significant difference could be demonstrated. In the multivariate analysis, the same 3 factors were independently associated with a worse SNL (Table 1 and Fig. 2).
In patients living with their native liver, 5- and 10-y SwsPHT were 65.3% (SE ± 5.0%, AR5y = 39) and 43.6% (SE ± 6.8%, AR10y = 7), respectively.
In the univariate analysis, 2 factors were associated with a worse SwsPHT: PPI >15 cm and the absence of postoperative normalisation of bilirubin level. Although SwsPHT decreased when the severity of liver fibrosis increased, no significant difference could be demonstrated. In the multivariate analysis, the same 2 factors were independently associated with a worse SwsPHT (Table 2 and Fig. 3).
In the patients whose bilirubin level normalized postoperatively, 5-y SwsPHT was 63.7% (SE ± 11.2%, AR5y = 3) when PPI was ≤15 cm and 51.6% (SE ± 14.8%, AR5y = 1) when PPI was >15 cm (P = 0.03) (Fig. 4).
Biliary atresia is characterized by obstruction of both extrahepatic and intrahepatic bile ducts of unknown origin, occurring in the perinatal period. The main features of liver histology are intense cholestasis with biliary plugs, ductular proliferation, and marked fibrosis. As compared with other causes of neonatal cholestasis, liver fibrosis is more severe in BA patients (24). Although a high degree of liver fibrosis at the time of the Kasai operation has been correlated with lower chances of restoration of the biliary flow, clearance of jaundice and SNL (13–18), the impact of initial liver fibrosis on the progression to threatening PHT remained unclear (19,20).
To simply evaluate the portal pressure during the Kasai operation and avoid sophisticated techniques or scoring systems, we determined a PPI measured after catheterisation of the umbilical vein, defined as the height of physiologic saline above the upper liver surface. This procedure proved to be feasible in most cases (89%) and safe (no complications). Portal pressure index was positively correlated with the age at Kasai operation and with the severity of liver fibrosis, as assessed by METAVIR and Chevallier's scores (21,22).
Our results show that elevated portal pressure, complete atresia of the extrahepatic biliary remnant and polysplenia syndrome were independently associated to a worse survival with the native liver. The deleterious impact of polysplenia syndrome on outcome has been shown in large series (9,25), whereas it was not found in smaller groups of patients (26,27). Similarly, the impact of the anatomy of the extrahepatic biliary remnant was confirmed in this series, as previously shown in others (8,9,11,28): Patients with complete extrahepatic biliary obstruction have lower chances of postoperative clearance of jaundice as compared with those with partial obstruction. The impact of age at Kasai operation did not reach statistical significance in this series. However, it has been clearly demonstrated that the chances of success of the Kasai operation decrease when the age at the time of surgery increases (8,9,11,28).
In the patients alive with their native liver, 2 factors were independently associated with a higher risk of later developing PHT: portal pressure at Kasai operation and postoperative normalization of bilirubin level. Patients with failed Kasai operation and progressing biliary cirrhosis consequently have a higher risk of developing PHT than patients with restored bile flow and stabilized liver disease. Our results show that elevated portal pressure at initial surgery also increases the risk of ulterior PHT, even in the patients whose postoperative bilirubin level returned to normal (Fig. 4). These findings suggest that patients with elevated portal pressure at initial surgery constitute a subgroup in which signs of PHT should be carefully searched for.
A tendency for worse SNL and for worse SwsPHT in patients alive with their native livers was observed when the severity of liver fibrosis at the time of Kasai operation increased. However, this tendency did not reach statistical significance, and PPI better predicted the outcome after the Kasai operation than did the liver fibrosis scores used in this study. This may be explained by several means. The spread of fibrosis is not homogeneous in the liver, and therefore, scores of fibrosis may be different in 2 biopsies simultaneously performed in 2 places of the same liver. Even if our specimen was large (median area, 15 mm2; median number of portal tracts, 22/biopsy), the studied samples only partly reflect the extent of fibrosis in the livers. Furthermore, the histological scoring is highly dependent on the experience of the pathologist (23). All histologies were reviewed by one single senior pathologist with a large experience in pediatric liver diseases; nevertheless, some subjectivity remained in the score attributed to each biopsy. Furthermore, no specific fibrosis scoring system is available for BA, and the scores we used were initially described for adult liver diseases: the METAVIR score for chronic hepatitis C (21) and the Chevallier's score for various liver diseases (22). In contrast, portal pressure reflects the whole of the intrahepatic resistances and is a measurable value without any interpretation. We deliberately chose a very simple method for evaluating portal pressure by measuring the PPI as a reading measurement above the upper liver surface. This method may provide some imprecision, which could possibly be reduced by direct measurement of portal pressure with a pressure measurement device. However, the reproducibility of the PPI measurement was checked in each patient.
Biliary atresia patients with elevated portal pressure at the time of Kasai operation have lower chances of success of this procedure and a higher risk of developing significant PHT in infancy and childhood, even if bilirubin levels normalize after the operation. Measurement of the PPI during Kasai operation is simple and safe and better predicts the postoperative outcome than do the histological scores of liver fibrosis.
The authors thank the pediatricians, surgeons, anesthetists, radiologists and pathologists (especially Dr Jeanine Quillard) of the Bicêtre pediatric team and Dr Michael Chilcott for revising the English translation of this article.
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