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Journal of Indian Association of Pediatric Surgeons

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Journal of Indian Association of Pediatric Surgeons
Wolters Kluwer -- Medknow Publications
Correlation of pre- and post-operative liver function, duct diameter
at porta hepatis, and portal fibrosis with surgical outcomes in biliary
atresia
Rajib Ray Baruah, Veereshwar Bhatnagar, [...], and Siddhartha Datta Gupta
Additional article information
Abstract
Background and Aims:
Extrahepatic biliary atresia is one of the most challenging conditions in
pediatric surgery. The definition of prognostic factors is controversial.
Surgical outcomes after bilioenteric drainage procedures are variable.
This study attempts to correlate the pre- and post-operative liver
histology with clinical factors in order to define early predictors of
success.
Materials and Methods:
Twenty consecutive patients, treated by Kasai's portoenterostomy (KP)
over a 3 years period were included in this study. Tissue obtained from
the porta hepatis was analyzed for duct size using an optical micrometer
and was categorized into three types: I-No demonstrable ducts; II - <50 μ;
III - >50 μ. Pre- and post-operative liver biopsy was analyzed for
architectural changes and fibrosis; hepatic fibrosis was quantified using
existing criteria. Pre- and post-operative liver function tests (LFTs) were
also done. Surgical outcomes were defined as: (A) Disappearance of
jaundice within 3 months; (B) initial disappearance of jaundice with
recurrence by 6 months and (C) persistence of jaundice. Duct diameters,
fibrosis score, and LFT were correlated with age and clinical outcomes.
Results:
The surgical outcomes were: A-6 patients (30%), B-6 patients (30%), C-8
patients (40%). The duct size at the porta was I-3 patients, II-11 patients,
and III-4 patients (tissue was not available in 2 cases). The change in total
serum bilirubin (mg%) from pre- to post-operative period was 13.6 ± 3.9
(Group A), 4.6 ± 2.8 (Group B), and 3.4 ± 3.9 (group C) (P < 0.001) and
direct and indirect fractions followed a similar trend; the changes in liver
enzymes were not significant. The changes in hepatic histopathological
changes (ballooning of hepatocytes, giant cells, cholestasis, portal tract
infiltration, ductular proliferation, lobular necrosis, and fibrosis) were
also not significant but there was a definite trend in the change in fibrosis
-1.500 ± 1.643 (Group A), 0.667 ± 2.582 (Group B), and 1.500 ± 1.852
(Group C) - reduction of fibrosis with good results and progression of
fibrosis with poor results.
Conclusions:
Following KP, jaundice persisted in 40% patients; it disappeared in 60%
patients but reappeared in half of these patients 6 months postoperatively.
The duct size at the porta hepatis did not correlate with age or surgical
outcome. Serum bilirubin showed the best correlation with surgical
outcome. Postoperative changes in hepatic fibrosis seem to have some
bearing on surgical outcomes-progressive fibrosis is a poor prognostic
factor.
KEY WORDS: Extrahepatic biliary atresia, hepatic fibrosis, Kasai's
portoenterostomy, liver biopsy, liver function test
INTRODUCTION
Extrahepatic biliary atresia (EHBA) is a challenge to pediatric surgeons.
It results from a destructive sclerosing inflammatory process of the
extrahepatic bile ducts and causes complete obstruction to bile flow.
Untreated biliary atresia ends in chronic liver disease with obliteration of
intrahepatic bile ducts progressing into biliary cirrhosis; there are no
survivors by 2 years of age.[1,2] The role of various factors believed to
be important for a successful outcome has been debated and these include
age at operation, size of bile ductules, degree of liver fibrosis, and the
need for external vents or anti-reflux conduits. The intraoperative
identification of prognostic factors is limited by a lack of established
criteria. In this study, an attempt has been made to correlate the
morphological features of liver biopsy specimens and tissue from the
porta hepatis taken at the time of Kasai's portoenterostomy procedure
(KP) and postoperative liver biopsy specimens of survivors with clinical
factors in order to determine the prognostic factors in the first 6 months
after surgery.
MATERIALS AND METHODS
This prospective study was conducted on 20 patients with EHBA,
diagnosed by preoperative ultrasonography, hepatobiliary scintigraphy,
and operative cholangiography and treated by KP over a 3 years period in
the Department of Pediatric Surgery, All India Institute of Medical
Sciences, New Delhi. There were 12 males and 8 females. The age
distribution was up to 1 month n = 1, 1-2 months n = 10, 2-3 months n =
8, and >3 months n = 1. All operative procedures were performed by the
same senior surgeon (VB). Postoperative cases were divided into three
groups according to their clinical outcome at 6 months after surgery
based on clinical findings:
Group A (Good): Patients in whom the jaundice cleared by 3 months
following KP.
Group B (Fair): Patients in whom jaundice cleared by 3 months following
KP but re-appeared before 6 months postoperatively in the absence of
cholangitis.
Group C (Poor): Patients who survived the surgery, but in whom the
jaundice never cleared.
Wedge biopsy specimen of liver and tissue excised from the porta hepatis
during KP, as well as postoperative liver biopsy specimens obtained by
Tru-Cut needle were made into 5 μ sections and subjected to
histopathological examination. The Tru-Cut needle biopsies were taken at
6 months after KP. All histopathological specimens were reviewed by the
same senior pathologist (SDG) who was blinded to the clinical results.
The following staining techniques were employed: Hematoxylin and
Eosin, Masson's Trichrome, reticulin, and diastase. The stained sections
were examined under light microscopy. Diagnostic criteria and a grading
system available in the literature were used to evaluate the histological
features.[3,4]
The ducts at the porta were classified into three types, according to the
diameter of the ducts.[3] An optical micrometer was used to measure the
internal diameter of the ducts. The mean of three measurements for each
structure was taken. The grading was as follows:
Grade I: No demonstrable ducts
Grade II: Duct size <50 μ
Grade III: Duct size >50 μ
Histopathological examination of the liver biopsy specimens included
ballooning of hepatocytes, presence of giant cells, cholestasis (cellular,
canalicular, and ductular), cellular infiltration of portal tracts, ductular
proliferation, lobular necrosis, and fibrosis. The fibrosis was evaluated in
detail and it was scored according to existing criteria[5,6] as follows:

0: No fibrosis

1: Fibrous expansion of some portal areas, with or without short fibrous
septa

2: Fibrous expansion of most portal areas, with or without short fibrous
septa

3: Fibrous expansion of most portal areas with occasional portal to portal
(P-P) bridging

4: Fibrous expansion of most portal areas with marked portal to portal (PP) bridging as well as portal to central (P-C) bridging

5: Marked bridging (P-P and/or P-C) with occasional nodules (incomplete
cirrhosis)

6: Cirrhosis, probable or definite
Preoperative liver function tests (LFTs) for review in this study included
serum bilirubin, transaminases (serum glutamic oxaloacetic transaminase,
serum glutamic pyruvic transaminase,) and alkaline phosphatase.
Postoperatively these were repeated 6 months after KP.
The clinical outcomes were correlated with ductular size, hepatic fibrosis,
and LFTs. The statistical analysis was done using STATA 9.0 (College
Station, Texas, USA) and appropriate tests of significance were used
where applicable; a P < 0.05 was considered significant.
RESULTS
Tissue from the porta hepatis was not available in 2 patients. Hence, this
was evaluated in 18 patients only. In 3 patients there were no ducts, in 11
patients the ducts were <50 μ (23.6-48.9 μ) and in the remaining 4
patients the ducts were >50 μ (50.0-209.0 μ).
The postoperative clinical outcome was good in 6 patients, fair in 6
patients, and poor in 8 patients.
The details of the histopathological examination of the tissue from the
porta hepatis in relation to age, hepatic fibrosis score, and clinical
outcome are presented in Table 1. The distribution was not statistically
significant. However, the majority of patients with ducts were seen in the
1-3 months age groups (13 of 18 patients). The severity of hepatic
fibrosis was independent of the duct size at the porta hepatis. The clinical
outcome also did not depend on the duct size at the porta hepatis.
Table 1
Histopathological examination of tissue from the porta hepatis
The details of hepatic fibrosis in pre- and post-operative liver biopsies in
relation to age and clinical outcome are presented in Table 2. The
distribution of patients was not statistically significant. Almost all
patients had some degree of fibrosis. Biliary cirrhosis was present in only
3 patients preoperatively, but postoperatively the fibrosis progressed to
biliary cirrhosis in 5 other patients. However, a few patients also showed
a reduction in the degree of fibrosis. Thus, it is clear that hepatic fibrosis
is a dynamic process; in some patients the fibrosis reduced while in
others it was progressive. There was no correlation between the clinical
outcome and the score of hepatic fibrosis. The existence of fibrosis at the
time of KP does not seem to affect the early results of surgery, although
there seems to be a trend toward poorer outcomes with higher degrees of
fibrosis.
Table 2
Pre- and post-operative hepatic fibrosis in liver biopsies
The details of pre- and post-operative LFTs have been presented in Table
3. There was a significant reduction in the postoperative serum bilirubin
(total, direct and indirect) as compared to the preoperative levels. The
change between pre- and post-operative bilirubin levels when compared
among the three outcome groups was also found to be statistically
significant. As expected, the decrease was highest in Group A and the
least in Group C for total, direct and indirect serum bilirubin (P < 0.001,
0.001 and <0.04 respectively). Thus, the establishment of bilioenteric
drainage and its effectiveness determines whether the clinical outcome is
good, fair or poor. This pattern was also evident in the changes in the
levels of alkaline phosphatase; in Groups A and B the postoperative
levels were lower than the preoperative levels but in Group C this pattern
was reversed. However, the changes between the three groups did not
reach statistical significance. The transaminases also showed a decrease
in the postoperative levels, but the differences in the changes between the
three groups did not reach statistical significance.
Table 3
Comparison of liver function between groups A, B, C
The various histological parameters (ballooning of hepatocytes, presence
of giant cells, cholestasis, portal inflammation, ductular proliferation, and
lobular necrosis) were compared in the pre- and post-operative biopsies
and within the three clinical outcome groups. There was no statistically
significant difference and there did not seem to be any pattern in the
distribution with regard to ballooning of hepatocytes, presence of giant
cells, and lobular necrosis. Increasing cholestasis, portal inflammation,
and ductular proliferation seemed to accompany worsening of clinical
outcome. However, portal fibrosis was seen to reduce almost significantly
in Group A patients postoperatively (P = 0.056), in Group B patients it
showed a slight increase and in Group C patients the increase in
postoperative fibrosis was almost significant (P = 0.056). However, the
change in the severity of fibrosis between the three groups was not
statistically significant. Among the various histological parameters
studied, the severity of portal fibrosis and its progression seemed to be
the only parameter which affected the clinical outcome [Table 4].
Table 4
Comparison of portal fibrosis score between groups A, B, C
DISCUSSION
The current management of EHBA follows the principle that bile
drainage may be established from residual microscopic channels in the
tissue at the porta hepatis.[5] Many studies have reported prognostic
factors for clinical outcome after hepatic portoenterostomy.
Histopathological features of the ductal remnants at the porta hepatis and
the liver have been correlated with the clinical outcome of the patients.
The presence of microscopically demonstrable ducts in the porta hepatis
and the duct size has been reported to be important, but this is not
universally accepted.[1,3,6,7] This study explores the possibility of
determining early indicators of prognosis in the first 6 months after
surgery.
In this study, there was no correlation between duct size and clinical
outcome. Some of the patients with bigger ductules had a poor clinical
outcome and some patients with no ductules in the porta had a good
clinical outcome.
It has been universally believed that duct size is inversely proportional to
the age at surgery that is, younger infants have larger ducts.[8,9]
However, several studies have disputed this correlation between age and
duct size.[3] This study also did not show any correlation between age
and duct size. In the group of patients aged 2 months or less, 8 of 10
(80%) patients either showed no ducts or ducts smaller than 50 μ. The
number of infants with ducts larger than 50 μ was similar (75%) in the
age group more than 2 months. Therefore, age in isolation should not be
used as a criterion to determine prognosis.
Parameters of hepatic histopathological features have also been used to
determine prognosis. Parenchymal degeneration and giant cell
transformation have been reported to be associated with early death.[10]
However, in another study no prognostic significance could be attributed
to fibrosis, inflammation, and giant cells.[1] In this study, the
histopathological parameters studied included ballooning of hepatocytes,
presence of giant cells, cholestasis, inflammatory infiltration, lobular
necrosis, and portal fibrosis. Except for portal fibrosis none of the other
parameters had any significance in determining prognosis in the first 6
months after surgery.
The histopathological findings on postoperative liver biopsy have been
reported as an important predictor of long-term prognosis.[11,12,13,14]
Reduction of fibrosis has been reported with establishment of good
biliary drainage and older infants tend to have greater fibrosis and this in
turn leads to poor prognosis. Progression of fibrosis is also a poor
prognostic sign. In the present study, it was evident that hepatic fibrosis
was a dynamic process and that good clinical outcomes resulted in a
reduction of fibrosis and increase in fibrosis accompanied poor clinical
outcomes. The severity of hepatic fibrosis in the postoperative period was
found to be independent of duct size at the porta.
The reduction in the levels of serum bilirubin is an obvious indicator of
clinical outcome as seen in this study. With good clinical outcome, the
levels of transaminases and alkaline phosphatase also show a fall which
may not be seen with poor outcome.
In 1975, Kasai et al. stated that a successful operative drainage might halt
the proliferation of bile ducts and lead to improvement in hepatic
architecture. They stressed on the importance of the following prognostic
factors:
1. Age at operation,
2. Size of bile ductules.
3. Degree of fibrosis in the liver.[15]
In this study, the age at surgery and duct size do not seem to have any
influence on the early outcome of surgery, although changes in hepatic
fibrosis during this period does indicate a prognostic significance. A
longer study will be required to establish whether the early predictors of
good outcomes may have any role in predicting long-term prognosis.
Footnotes
Source of Support: Nil
Conflicts of Interest: None declared.
Article information
J Indian Assoc Pediatr Surg. 2015 Oct-Dec; 20(4): 184–188.
doi: 10.4103/0971-9261.161040
PMCID: PMC4586981
PMID: 26628810
Rajib Ray Baruah, Veereshwar Bhatnagar, Sandeep Agarwala, and Siddhartha Datta
Gupta1
Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi,
India
1Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
Address for correspondence: Prof. Veereshwar Bhatnagar, Department of Pediatric
Surgery, All India Institute of Medical Sciences, New Delhi - 110 029, India. Email: [email protected]
Copyright : © Journal of Indian Association of Pediatric Surgeons
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