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Ratio of preoperative and postoperative serum bilirubin levels predicts early

outcome following biliary atresia surgery

Kashish Khanna1, Veereshwar Bhatnagar1, Sandeep Agarwala1, Maddur


Srinivas1, Siddhartha Datta Gupta2
1 Department of Pediatric Surgery, All Institute of Medical Sciences, New

Delhi, India
2 Department of Pathology, All Institute of Medical Sciences, New Delhi, India

Date of Web 29-Mar-


Publication 2018

Aim: This study investigates the fall in total serum bilirubin levels within 1
week after surgery, as a marker to predict early outcome in biliary atresia (BA)
patients post-Kasai portoenterostomy (KP).
Methods: The ratio of total serum bilirubin levels at the 7th postoperative day
to the preoperative level (TB7/TB0) in patients undergoing KP was calculated
(January 2011–July 2015). Patients were stratified after 3-months follow-up
into outcome groups depending on the clinical clearance of jaundice and
TB7/TB0 ratio was correlated to outcome and liver histopathological changes
in these groups.
Results: Sixty-one patients (M:F = 44:17), median age 75 days were
included. At the end of 3 months, 27 (44.39%) were anicteric while 26 (42.6%)
were still clinically jaundiced. Patients with a higher median value of TB7/TB0,
that is, 0.856 were more likely to have jaundice at the end of 3 months as
compared to patients with a lower median value of 0.615 (P < 0.0001). A
cutoff TB7/TB0 ratio >0.723 predicted the KP outcome with 84.6% sensitivity
and 81.5% specificity. The difference in TB7/TB0 ratio between patients with
varying severity of liver histopathological changes was also significant,
namely, cholestasis (P = 0.01), hepatocellular damage (P = 0.03), portal
inflammation (P = 0.04), and portal fibrosis (P = 0.02).
Conclusions: The rapidity of fall in the total serum bilirubin levels within 1
week post-KP was able to predict the likely outcome in BA patients.

Keywords: Biliary atresia, Kasai portoenterostomy, serum bilirubin, surgical


outcome

How to cite this article:


Khanna K, Bhatnagar V, Agarwala S, Srinivas M, Gupta SD. Ratio of
preoperative and postoperative serum bilirubin levels predicts early outcome
following biliary atresia surgery. J Indian Assoc Pediatr Surg 2018;23:81-6

How to cite this URL:


Khanna K, Bhatnagar V, Agarwala S, Srinivas M, Gupta SD. Ratio of
preoperative and postoperative serum bilirubin levels predicts early outcome
following biliary atresia surgery. J Indian Assoc Pediatr Surg [serial online]
2018 [cited 2019 Feb 16];23:81-6. Available
from: http://www.jiaps.com/text.asp?2018/23/2/81/228890

Introduction

Biliary atresia (BA) is a rare but serious condition with an incidence of 1 in


10,000–1 in 16,700 live births where pathological jaundice persists beyond 2
weeks of life.[1],[2] If left untreated, it has a relentless course to chronic liver
disease with progressive obliteration of the intrahepatic biliary tree and liver
cirrhosis with essentially no survivors by the age of 2 years.[3] Kasai
portoenterostomy (KP) is the primary therapeutic option for establishing biliary
drainage. About 25% of the total patients undergoing KP will be cured, and in
the remaining patients, progressive liver failure develops that can be salvaged
only by transplantation.[4],[5],[6]

Many studies have focused on the prognostic factors both biochemical and
histopathological associated with the KP but it is still controversial as to which
of these indicators will predict a successful or failed KP. These include
bridging fibrosis, extensive liver fibrosis, direct bilirubin (DB) levels and
aspartate aminotransferase levels 2 months after KP, gamma-glutamyl
transferase, and bilirubin levels at 5 weeks after KP.[7],[8],[9],[10],[11],[12]

The most pressing question after KP is whether the child is likely to be treated
successfully leading to a cure or will progress to chronic liver disease and
require liver transplantation (LT). Due to the lack of defined objective criteria,
it is not possible to give an objective prognosis in the early postoperative
period. This is particularly a difficult situation for the parents of these children.

A successful KP is defined by the clearance of clinical jaundice and a fall in


the total serum bilirubin levels to normal value postoperatively. We
hypothesized that the rapidity of fall in total serum bilirubin in 1 week should
be able to predict the long-term outcome of KP.

This study was conducted to seek a simple ratio of serum total bilirubin at the
7th day postoperative to its preoperative levels (TB7/TB0) as a marker to
predict early, the outcome of children with BA undergoing KP. A relationship
between the severity of the histopathological changes in liver biopsy and the
TB7/TB0 ratio was also studied.

Materials and Methods


The study was approved by the Ethics Committee of All India Institute of
Medical Sciences vide letter number IESC/T20/03.01.2014. All patients who
were diagnosed with extrahepatic BA and who underwent KP during January
2011 to July 2015 were included. Patients whose parents did not give consent
for the study, who were lost to follow-up or those who died before 3 months of
follow-up were excluded from this study. The patients were evaluated
clinically, biochemically, and radiologically at presentation. Data of
age/gender, symptoms (discoloration of skin or sclera/clay colored or mixed
stools/high-colored urine/abdominal distension), signs
(icterus/hepatomegaly/splenomegaly/ascites), abdominal ultrasonography,
hepatobiliary scan, biochemical liver function tests, and total serum bilirubin at
the 7thpostoperative day were collected. The TB7/TB0 ratio was calculated for
each patient.

During KP, a wedge biopsy of the liver was taken and sent for
histopathological evaluation. All the liver biopsy samples were stained with
hematoxylin and eosin and were analyzed by a single senior hepatobiliary
pathologist. The intraoperative wedge biopsy of the liver was histologically
graded according to the histological scale as described previously.[13]

The patients were followed up for clinical disappearance of jaundice, the color
of the stools, and the serum bilirubin levels. On this basis, they were stratified
into three outcome assessment groups separately at the end of 3
months [Table 1].

Table 1: Outcome group according to clinical


jaundice, color of stools, and serum bilirubin
levels

Click here to view

The statistical analysis was carried out using STATA 11.0 (College station,
Texas, USA). The data were presented as number (percentage) or mean ±
standard deviation/median (minimum-maximum) as appropriate. The change
in clinical jaundice at 3 months from 1 month was compared using McNemar's
test. The difference in median TB7/TB0 was compared with severity of
histological changes using Kruskal–Wallis test. The difference in medians of
TB7/TB0 was compared with the outcome using Wilcoxon rank-sum test. The
predictive ability of TB7/TB0 was calculated for the clinical outcome using
receiver operating characteristics (ROC) curves. The results are presented as
cutoff, sensitivity, specificity, rate of correct classification, likelihood ratio, and
area under the ROC curve (AUC), 95% confidence interval. The P < 0.05 was
considered statistically significant.

Results
A total of 61 patients, 44 (72.1%) males and 17 (27.9%) females who
underwent KP for BA were included in this study; 5 died and 2 were lost to
follow-up. Fifty eight patients were followed up till 1 month and 54 till 3 months
postoperatively. The mean age of presentation was 83.9 ± 35.9 days, median
75 days with the youngest child 24 days old and the oldest 165 days.

All children presented with jaundice and high colored urine. All patients had
hyperbilirubinemia with the mean bilirubin level of 11.6 ± 4.1 mg/dl and
median of 10.1 mg/dl ranging from 6.2 to 25 mg/dl.

Liver histopathology revealed that all patients had cholestasis with Grade 2
cholestasis in most of them -44 (72.1%). Hepatocellular damage Grade 1
(ballooning degeneration) was present in 15 (24.6%), Grade 2 (feathery
degeneration) in 38 (62.3%), and Grade 3 (necrosis) in 8 (13.1%) patients.
Most liver biopsy specimen showed moderate bile duct proliferation- 39
(63.9%). Almost equal proportions of patients had Grade 1 (mild), Grade 2
(moderate) and Grade 3 (severe) degrees of bile duct inflammation. All cases
showed some degree of portal edema and portal inflammation. Most of the
patients 46 (75.4%) had severe degree of fibrosis.

At the end of 1 and 3 months, 18 (31.0%) and 27 (50.0%) patients,


respectively, were clinically free from jaundice. While the remaining 40
(68.9%) and 27 (50%) continued to have jaundice at the end of 1 and 3
months, respectively. Similarly, 35 (61.4%) patients and 34 (62.9%) patients
had cholic or yellow-colored stools at the end of 1 and 3 months, respectively.
At the end of 3 months, 54 patients had a mean of 5.2 ± 4.2 mg/dl, median 4.0
mg/dl of the total serum bilirubin, and it ranged from 0.4 to 16.2 mg/dl.

The TB7/TB0 ratio was calculated for all the 61 patients and the mean value
was 0.73 ± 0.19, median 0.74, and ranged from a minimum of 0.25 to a
maximum of 1.09. The outcome groups were divided on the basis of clinical
and biochemical parameters as described above. Of the 54 patients, 27
(44.3.9%) were free of jaundice clinically at the end of 3 months, while 26
(42.6%) were clinically jaundiced at the end of 3 months. One patient had no
clinical jaundice at the end of 1 month of follow-up but developed jaundice
later at 3 months of follow-up. He was excluded from the analysis. Of the 54
patients, 34 (63.0%) had yellow-colored stools and 17 (31.5%) had clay-
colored stools at the end of 3 months. Three patients had yellow stools at the
end of 1 month, but later at 3 months, had clay-colored stools. Of the 54
patients, 23 (42.6%) had normal total serum bilirubin levels at the end of 3
months, and the remaining 31 (57.4%) had elevated serum bilirubin levels at
the end of 1 month and at the end of 3-month postoperatively.

When the TB7/TB0 ratio was compared with the KP outcome, it was found
that patients with a higher median value (0.856) of TB7/TB0 had significantly
higher chances of persistence of clinical jaundice at the end of 1 month and at
3 months as compared to patients with a lower median value (0.615) of
TB7/TB0 (P ≤ 0.0001). Similarly, it was found that patients with a higher
median value (0.884) of TB7/TB0 had significantly higher chances of the
persistence of clay-colored stools at the end of 1 month and 3 months as
compared to patients with a lower median value (0.623) of TB7/TB0 (P =
0.0001). Patients with a higher median value (0.818) of TB7/TB0 had
significantly higher chances of elevated serum bilirubin levels at the end of 1
month and at 3 months as compared to patients with a lower median value
(0.575) of TB7/TB0 (P ≤ 0.0001) [Table 2].

Table 2: Relation of TB7/TB0 ratio with the


outcome

Click here to view

TB7/TB0 as a marker to predict early outcome post-Kasai portoenterostomy


using receiver operating characteristics curve analysis

The ROC curve analysis was applied to find a cutoff value of TB7/TB0 for
each of the outcome. The area under the curve was highest for
disappearance of clinical jaundice out of all the three outcomes which means
the TB7/TB0 predicts clearance of clinical jaundice better than the color of
stools and the bilirubin levels at follow up [Figure 1].
Figure 1: Receiver operating characteristics
curve showing the predictive ability of TB7/TB0
ratio using clinical outcomes, namely, (a) clinical
jaundice, (b) color of the stools, and (c) total
serum bilirubin. Sn: Sensitivity, Sp: Specificity,
CC: Classified correctly, LR: Likelihood ratio,
NPV: Negative predictive value, AUC: Area
under the curve, CI: Confidence interval

Click here to view

It was observed that if TB7/TB0 is >0.723, then the negative predictive value
(NPV) was 84.6%. It implies that if the TB7/TB0 is <0.723, clinical jaundice
will clear in 84.6% of the patients at the end of 1 and 3 months. Furthermore,
if TB7/TB0 ratio >0.723, it predicts the persistence of clinical jaundice at 1
month and at 3 months with the sensitivity and specificity of 84.6% and
81.5%, respectively.

The cutoff of TB7/TB0 ratio >0.758 predicted the presence of clay-colored


stools at 1 month and 3 months with the sensitivity and specificity of 82.4%
and 79.4%, respectively. This implies that if the TB7/TB0 is <0.758, then the
child is likely to pass cholic stools at the end of 1 and 3 months in 90% of the
cases (NPV 90%).

A cutoff of TB7/TB0 ratio >0.706 predicted the presence of elevated bilirubin


at 1 month and 3 months with the sensitivity and specificity of 80.7% and
78.3%, respectively. It was found that if the TB7/TB0 is <0.706, the serum
bilirubin will be normal at the end of 1 and 3 months in 75% of the patients
(NPV 75%) [Figure 1].

Relation of TB7/TB0 with the histological changes

The difference in the TB7/TB0 ratio between patients with varying severity of
cholestasis (P = 0.01), hepatocellular damage (P = 0.03), portal inflammation
(P = 0.04), and portal fibrosis (P = 0.02) was significant. However, the
difference in TB7/TB0 ratio was not significant among patients with varying
severity of bile duct proliferation (P = 0.07) or with portal edema (P =
0.08) [Table 3]a and [Table 3]b.
Table 3a: Relation of histological characteristics
with TB7/TB0 (n=61)

Click here to view

Table 3b: Relation of portal fibrosis (Okhuma's


classification) to TB7/TB0 (n=61)

Click here to view

Discussion

BA patients if left untreated, die of hepatic decompensation, esophageal


variceal bleeding, or infection within 19 months.[1] Some degree of hepatic
fibrosis is invariably present at initial surgery and can be graded histologically.
About 25% of infants improve after KP and can live a near normal life. The
remaining may progress to liver failure that can be salvaged only by LT. [4],[5]

Predictive markers of successful Kasai operation

The results of liver transplantation for BA were reported to be poorer in


children who had previously undergone a Kasai operation. [14] Arguments
against a primary liver transplant suggested that it would deprive some
children of the possibility of living with the native liver while the long-term
effects of immunosuppression over decades of life are still unknown.
Furthermore, a primary liver transplant would obviously dramatically increase
the need for donor organs at a time when the shortage of organs is still an
unresolved problem.[10] In many countries, facilities for pediatric liver
transplantation are not well developed. The ability to reliably predict outcomes
would be invaluable when planning the management of BA, that is, early
referral to a transplant center, optimization of medical and nutritional therapy,
education and counseling of the parents, etc.

In a retrospective study by Rodeck et al., the ROC analysis determined a


cutoff for bilirubin concentrations of 57 μmol/l at 6-week postoperatively for
event-free survival with a sensitivity of 80% and a specificity of 78.6%. The
hepatic iminodiacetic acid scan excretion values at 6-month postoperatively
were also compared. The 5-year event-free survival rate was found to be
100% in the group with good tracer excretion and a bilirubin concentration of
<57 μmol/l and 27% for the other group (log-rank test, P < 0. 0001).[9]

Another study by Baruah et al.,[15] in 2015, supports the same conclusion that
the reduction in the levels of serum bilirubin is an obvious indicator of clinical
outcome as seen in this study. With the good clinical outcome, the levels of
transaminases and alkaline phosphatase also show a fall that may not be
seen with poor outcome. However, no clinical cutoff value of liver function
tests was suggested.

Goda et al.[7] studied 54 patients of BA and determined cutoff values of the


liver function test. The most reliable cutoffs determined by ROC analysis in
this study were DB of 0.7 mg/dl at 2 months (sensitivity: 93%, specificity:
75%) and aspartate transaminase (AST) of 94 IU/L at 2 months (sensitivity:
87%, specificity: 71%). The 54 cases were divided into three subgroups
according to the cutoff values: Group G (good) with DB and AST < cutoffs (n =
16; Group I: II = 1:15), Group M (moderate) with DB or AST > cutoffs (n = 9;
Group I: II = 4:5), and Group P (poor) with DB and AST ≥ cutoffs (n = 29;
Group I: II = 25:4). The 15-year survival rate in Groups G, M, and P was 94%,
44%, and 22%, respectively (P< 0.001). A combination of serum DB and AST
at 2 months after Kasai's operation was found to be a reliable predictor of
long-term BA outcome.

Yanchar et al.[8] also reported a predictive value of bilirubin 4-month


postoperatively as the earliest time for predicting prognosis. The bilirubin
concentrations described ranged from 14 to 46 μmol/l, and the rate of bilirubin
decline was 2.6 ± 1.5–10.8 ± 3.0 μmol/l/d, respectively. Other parameters of
liver function tests apart from serum bilirubin have also been studied as
predictive factors.

In this study, TB7/TB0 proved to be a simple marker for predicting early the
probable outcome post KP. The clearance of clinical jaundice was taken as
the most important parameter out of all the three. The ROC curves comparing
the ratio with the outcome parameters showed that the plot with clinical
jaundice had the maximum AUC. The difference in TB7/TB0 ratio between
patients with persistence of jaundice at the end of 3 months as compared to
patients who were jaundice free at 3 months was significant. If the TB7/TB0 is
<0.723, clinical jaundice is likely to clear at the end of 1 month in 84.6% of the
patients (NPV = 84.6%). In other words, patients with TB7/TB0 ratio of more
than 0.72 are 4.5 times more likely to have persistent clinical jaundice 3
months following KP (sensitivity of 84.6% and specificity of 81.5%).

It has been believed that the prognosis following KP worsens when the age of
the child at surgery is higher.[16]However, other studies [15],[17] have reported
that age at surgery did not have any significant influence on clearance of
jaundice; rather liver histology has a greater impact and liver histology did not
seem to have any correlation with age. Nio et al.[18] conducted a study on
more than 1000 patients and observed that there was no influence of age up
to 90 days on the clearance of jaundice. Moreover, a considerable percentage
of patients who underwent late portoenterostomy (after 90 days of life)
survived with their native livers for 5 and 10 years. Davenport et al.[19] also
showed that age of surgery had no effect on isolated BA as compared to
those with associated cysts or splenic malformation.

In the study being reported, it was found that cholestasis was present in all
patients and hepatocellular damage of moderate degree was present in
majority (62.3%) of the patients. Similarly, 63.9% and 55.7% patients had
moderate degree of bile duct proliferation and portal edema, respectively. All
patients had bile duct inflammation with almost equal distribution of patients in
the mild, moderate, and severe groups. Portal inflammation was moderate to
severe in more than half of the patients. When the TB7/TB0 ratio was
compared with the severity of histopathological changes, it was found that the
difference in TB7/TB0 ratio between patients with varying severity of
cholestasis, hepatocellular damage, portal inflammation, and portal fibrosis
was significant. However, the difference in TB7/TB0 ratio was not significant
among patients with varying severity of bile duct proliferation and portal
edema.

Conclusions

The rapidity of fall in the total serum bilirubin level within 1 week was able to
predict the outcome post-KP. This TB7/TB0 ratio is easy to calculate and can
be used objectively to explain to the parents the expected result of Kasai
operation within 7 days of surgery or at the time of discharge from the
hospital. This would further ensure early enrollment of the expected poor
outcome cases in the liver transplant program. Hence, the ratio of total serum
bilirubin on the 7th postoperative day to its preoperative levels is a reliable
marker to predict early, the outcome following surgery in BA patients. The
long-term outcomes including overall survival of these children with their
native liver, survival at 2- and 5-year follow-up, bilirubin at 2- and 5-year
postoperatively are still being studied.

Acknowledgment

The completion of this project would not have been possible without the
support and assistance of the doctors, nursing staff, and technical staff of the
Pediatric Surgery Department at AIIMS, New Delhi. We would like to thank Dr.
Rajni Yadav for the help in histopathological grading of biopsy samples, Mrs.
M Kalavani for performing the statistical analysis, and Dr. Vikram Khanna and
Dr. Anjan Dhua for their unconditional support and guidance throughout this
research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Recent Trends in the Diagnosis and Management of Biliary Atresia in Developing
Countries

Biliary atresia (BA) is a progressive obstructive cholangiopathy of both the intra- and extra-
hepatic biliary tree, leading to cholestasis and cirrhosis. It usually manifests in the first few
months of life with jaundice, pale stools, high colored urine and hepatomegaly. The
etiopathogenesis of BA is multifactorial, and its incidence has been reported to vary from
1:9000 to 1:15000 [1,2]. It is fatal if left untreated in first 2 years of life.

Diagnosis of Biliary Atresia

BA must be suspected in all neonates in whom jaundice persists after the period of physiologic
hyper-bilirubinemia (first 14 days of life). Jaundice is the only symptom of BA in the neonatal
age group. The diagnosis is delayed because of failure to differentiate jaundice due to liver
disease from physiologic jaundice. Delay in diagnosis is unfortunate since treatment is most
effective in this age group (before 30 days of life). Two distinct types of BA have been identified
– the embryonic or syndromic type, where associated extrahepatic malformations are present
and there is no jaundice-free interval; and the perinatal or isolated type, where there may be a
jaundice-free interval [3]. Extrahepatic malformations or Biliary Atresia Splenic Malformation
Syndrome (BASM) include splenic abnormalities like polysplenia and asplenia, cardiac defects,
situs inversus, intestinal malrotation, portal vein anomalies and inferior vena cava interruption.

Delay in referral in BA is because of difficulties in differentiating it from physiologic jaundice and


identifying an abnormal stool colour. This is a major problem in most parts of the world,
especially in developing countries. In India, only 20% of cases that present in most centers are
aged less than 60 days [4]. The parents of children with delayed diagnosis usually consult a
doctor for persistence of jaundice but a lack of awareness leads to the delay. Both primary
health care workers and primary care physicians must be aware of the need to refer infants in
whom jaundice persists beyond 14 days of age. It is also vitally important to identify abnormal
stool color and investigate infants in whom pale stools persist for 3 consecutive days [5]. Stool
cards have been effectively used as a screening tool in countries like Taiwan and Japan [6,7].
The stool card is incorporated in every child health booklet given to the parent at the time of
delivery. Abnormal stool colour is reported by the parent or pediatrician to the registry center
within 24 hours. In Taiwan, the sensitivity of detecting BA using stool cards improved from 72%
to 91% in the span of a single year [6]. Japan also reported a sensitivity of 76.5% and
specificity of 99.9% for the stool colour card in the diagnosis of BA [7]. Hence it will be useful
for developing countries to use this model and disseminate information about stool cards to
primary care physicians and healthcare workers. The onus of responsibility lies with national
pediatric forums to institute a nationwide screening program and play an active role like the
yellow alert poster campaign which created awareness among paediatricians throughout the
country [5].

Most children with BA have a normal postnatal weight gain and development. The classic triad
of jaundice, pale stools and high coloured urine may not be present early in the course of the
disease. The liver is firm, and in the initial stages splenomegaly and ascites which are features
of portal hypertension may not be obvious. The deceptively "well baby’’ is another reason for
delay in referral. Laboratory parameters show a rise in serum bilirubin with a raised conjugated
fraction (>50% of the total) and elevated transaminases. However, these findings are common
to most forms of neonatal cholestasis. A raised gamma glutamyl transferase (GGT) is seen in
BA, and is often used to differentiate it from neonatal hepatitis. A GGT level of >300 IU/L has a
specificity of 98.1% in the diagnosis of BA [8]. There may be an initial coagulopathy responsive
to Vitamin K. Persistent coagulopathy and hypoalbuminemia are features of advanced disease
and signify synthetic dysfunction of the liver.

Ultrasonography has gained importance as a key diagnostic tool for BA, and has an overall
accuracy of 98% [9]. However, this is operator-dependent and can be achieved only in centers
where dedicated pediatric sonologists are available. Radionucleotide scintigraphy (Tc99-HIDA
scan) has a high sensitivity but poor specificity in differentiating BA from other causes of
neonatal cholestasis [10]. It also requires pre-treatment of the infant with phenobarbitone for 3
days prior to the scan and repeated imaging for up to 24 hours to look for isotope activity in the
gut. Endoscopic retrograde cholangiopancreatography (ERCP) is technically difficult in young
infants and its results are also operator-dependent.
Liver biopsy showing portal tract expansion with edematous fibroplasia and proliferation of
anastomosing ductules is suggestive of BA if reported by an experienced histopathologist
(Fig. 1). Several Indian studies have reported high accuracies of over 85% for liver biopsies in
the diagnosis of BA [11-13]. These studies are from specialist centers with experienced
pathologists, and hence the diagnostic accuracy is high [14]. Children with biliary atresia have a
nonspecific biopsy diagnosis in as much as 15% of cases [15]. Therefore, in developing
countries, relying on a liver biopsy to make a conclusive diagnosis may lead to missed diagnosis
of BA in a significant number of children.

Fig. 1 Trucut liver biopsy showing portal tract expansion with edematous fibroplasia and proliferation of anastomosing ductules (H&E,
×40).

The gold standard for the diagnosis of BA is a per-operative cholangiogram which has a
diagnostic accuracy of 100%. The procedure involves injecting radio opaque contrast into the
gall bladder remnant through a small laparotomy. A diagnosis of BA is made if contrast does not
fill the common hepatic duct and intrahepatic ducts. Based on this per-operative cholangiogram,
BA is divided into three types according to the Ohi classification with the commonest type being
type 3 (Fig.2) [16]. If the cholangiogram shows a normal extrahepatic biliary tree, a wedge
biopsy of the liver is taken and the wound closed. Per-operative cholangiogram has to be
undertaken by an experienced surgeon who can differentiate hypoplastic ducts (Alagille
syndrome) from atretic ducts thereby avoiding a potentially damaging and unnecessary
operation in the former [17].
Fig. 2 Ohi classification of biliary atresia. CBD – common bile duct, CHD –common hepatic duct,
GB – gall bladder.

To summarize, in an infant with jaundice, pale stools, conjugated hyperbilirubinemia and raised
GGT, it is reasonable to perform an ultrasound scan and a liver biopsy to make a diagnosis of
BA. In developing countries, where such expertise may not be available in most centers, the
child should be referred for a per-operative cholangiogram and liver biopsy at the earliest
suspicion of BA. A screening program with stool color card is a must for early diagnosis and
should be the priority of healthcare systems. It is equally important to educate primary
physicians and healthcare workers about early diagnosis of cholestatic jaundice and to establish
a uniform protocol for its management [5].

Management of Biliary Atresia

The treatment of BA involves a sequential strategy combining Kasai Portoenterostomy (KPE) as


first line and Liver transplantation as second line treatment if KPE fails to establish bile flow
and/or progressive liver fibrosis and cirrhosis occurs (Fig. 3).
Fig. 3 Flow chart for the management of children with biliary atresia.

Kasai Portoenterostomy

Described by Professor Morio Kasai in 1959, the goal of this operation is to allow bile from the
liver to drain into the small intestine [18]. This operation has undergone several modifications
since it was first described and the outcomes have also vastly improved with the use of surgical
loupes for magnification and fine sutures for the anastomosis. We prefer a technique which
involves division of the left triangular ligament which enables the liver to be partially
exteriorized to expose the hilum. The remnant gall bladder is mobilized from its bed and excised
along with the biliary remnants. These remnants are meticulously dissected above the
bifurcation of the portal vein towards the corners of the hilar ductal plate, where the portal vein
and hepatic artery bifurcate into their branches. The dissection of the ductal plate begins from
the point where the right hepatic artery divides into its anterior and posterior branches, and
continues to the left where the left branch, of the portal vein joins the umbilical vein in the Rex
recess. The fibrous remnant in the region of the ductal plate is excised using sharp dissection
down to the level of the Glisson’s capsule (Fig. 4). Bile is usually found to drain from the right
and left corners of this ductal plate. A Roux loop of jejunum is anastomosed around this region
to the quadrate and caudate lobes of the liver. Using this technique it is possible to achieve
clearance of jaundice in over 50% of children [19,20].
Fig. 4 Operative picture of Kasai portoenterostomy showing fibrous biliary remnant (star),
hepatic artery (thin arrow) and portal vein (thick arrow).

Outcome of KPE

The outcome of KPE is evaluated by the clearance of jaundice (S. bilirubin <2 mg/dL) in 3
months, and the survival of children with their own liver: Native liver survival rate (NLSR).
Jaundice clearance leads to alleviation of hepatic fibrosis and the jaundice disappearance rates
(JDR) in most series from Japan, France, England and Wales is around 57% [1,19,21]. In 2003,
the Japanese Biliary Atresia Registry reported that nearly 53% of children had their own native
liver at the end of 10 years [1]. The 10 year NLSR reported from England and Wales in 2011
was 40% [20]. Most studies have shown that 45% of all children will reach their teenage years
with their own livers, and 30% will have a truly long-term, symptom-free life with normal liver
biochemistry [22-26]. Studies from specialized centers in India have also shown good JDR and
NLSR [4,27-30]. In the experience of 26 children from our center over the last 2 years, the JDR
was 50% (unpublished data).

Factors affecting the outcome of KPE


Several factors have been shown to adversely affect the outcome of KPE. The outcome is worse
in the embryonic or syndromic form compared to the perinatal form because this form
represents an early origin of the disease [3]. Ohi type 3 pattern of atresia, the commonest form
of BA, is associated with a poor outcome because in this variant the hilar ductules are also
atretic in addition to the extrahepatic biliary system [16]. Histological features such as ductal
plate malformations [31], cystic dilatation of intrahepatic biliary system [32] and bile lake
formation [33] are all associated with poor outcomes. Ductal plate malformations represent the
persistence of embryonic ductal structures. Their presence in the liver adversely affects the
outcome of KPE because they represent an early severe form of the disease [34].

Portal plate ductules measuring greater than 200 microns were found to correlate with the
success of KPE in some studies [27,35]. However, other studies have shown that the size of
ductules at portal plate did not have a linear relationship with prognosis [36,37]. Recent studies
from India have also shown no correlation between duct diameter and outcome [28,29]. Also,
accurate measurement of the size of bile ducts at the portal plate depends on the orientation of
the pathology specimen and there can be a subjective variation among pathologists [38].
Aspartate aminotransferase-to-platelet ratio index (APRi) has been used as a surrogate marker
for liver fibrosis. A cut-off value of 1.22 has shown to have 75% sensitivity and 84% specificity
for macroscopic cirrhosis. Hence, APRi at the time of KPE is a useful adjunct in evaluating
severity of liver disease in BA [39]. It also helps to predict native liver survival by reflecting
portal myofibroblastic cell activation, fibrogenesis and associated neovascularisation [40].

Age at KPE is an important determinant of jaundice clearance. Data from the Japanese Biliary
Atresia Registry reported a good outcome in infants who had KPE earlier than 30 days of age,
and a poor outcome after 90 days [1]. Between 30 and 90 days, age at KPE had no impact on
outcome. The French National Study reported a definite advantage in performing an early KPE
[21]. A recent study from India also showed better outcome of KPE when performed before
three months of age [27]. Early diagnosis is important because KPE before 90 days offers a
significant advantage in terms of post-operative jaundice disappearance and long term native
liver survival [41].

In infants older than 90 days, there is still a significant benefit in performing KPE. Studies have
shown JDRs of up to 48% and 10 year NLSRs of up to 40% in these children [1,26,41-43].
Successful KPE has been reported even until the age of 141 days [44]. The performance of KPE
after 3 months of age is justified in selected cases because it may obviate the need for liver
transplantation. There is a significant advantage to performing KPE even in older children with
BA; age alone is not a contraindication. The national consensus report recommended that
referring doctors need to be educated that there is no cut-off for late referral [14]. It is up to
the specialists (pediatric hepatologists and surgeons) to decide if the child has synthetic liver
failure, and hence will not qualify for a KPE.

Another factor that impacts the outcome of KPE is the surgical technique. The success of the
operation depends on the meticulous dissection of the liver hilum and the resection of the biliary
remnant [45]. Results are better after centralization of management of BA, and upto 24%
improvement in outcome can be achieved if the surgery is done in a specialized center [2,19-
21]. McKiernan, et al. [2] reported that the outcome of KPE was better in centers having case-
loads greater than 5 cases per year. In such specialized centers, the outcome of KPE in children
over 90 days was also better [46]. In the national consensus report, it was proposed that the
surgical treatment of children with BA should be contemplated only in centers performing at
least 6 KPEs a year. Since centers that fulfil this criteria are limited, more and more surgical
departments should be encouraged to develop proficiency in handling these cases [14]. In the
developing world, where health care systems do not provide for the costs of liver transplant,
centralization of management of infants with BA can significantly reduce the need for
transplantation [19].

Contraindications to KPE

The only contraindication to KPE is advanced liver disease with an uncorrectable coagulopathy,
low albumin, ascites and portal hypertension. The operation is associated with a very high
morbidity and mortality in this group because rapid decompensation of liver disease can occur.
Approximately 50% of children with BA will be able to clear jaundice, if KPE is performed by
experienced surgeons before the onset of advanced liver disease. These children have a
reasonable expectation of long-term survival to adulthood with a good quality of life [22].

Postoperative management
The incidence of cholangitis can be as high as 50% for the first two years after KPE [47].
Repeated episodes of cholangitis can lead to early liver failure. Episodes of cholangitis are
characterized by fever, recurrent pale stools and septicemia. However, sometimes fever may be
the only symptom. Prompt diagnosis followed by intravenous antibiotics for two weeks is
required if a pathogen can be identified in the blood or ascitic fluid. Long-term prophylaxis is
required with rotating antibiotics in cases of recurrent cholangitis [46]. Post-operative
corticosteroids to maximize bile flow has not been found to be of any use in improving the
outcome of KPE [48].

These infants also have multiple nutritional deficiencies, and supplementation with Vitamins A,
D, E and K is needed. They also have deficits in protein metabolism with low muscle and liver
stores of glycogen, which must be supported by feeding regimes to maximize growth potential
by providing adequate nutrition [49].

Liver Transplantation

Liver transplantation remains the cornerstone of long-term management of children with BA,
and is the commonest indication for transplantation in children. It is needed in more than 50%
of children with BA even after undergoing KPE.

Indications

Liver transplantation is indicated in BA in three different clinical settings. It may be necessary in


infants who have a delayed diagnosis of BA, and hence have not been subjected to a KPE. These
children usually present within one year of age with intense jaundice, liver synthetic dysfunction
and failure to thrive. The second group of children are those who undergo a KPE but do not
clear synthetic failure. These children usually need transplantation in the first two years of life.
The indications in this group include jaundice, portal hypertension and failure to thrive. The
third group of children (or adults) are those who have successfully cleared jaundice after the
KPE, but have recurrent cholangitis, portal hypertension or hepatopulmonary syndrome. Each of
these three groups of patients have their own specific set of issues and challenges during
transplantation.

General considerations

The majority of children with BA undergoing liver transplantation are less than two years of age.
These children usually weigh less than 10 kg and may even be less than 5 kg, especially those
with late diagnosis. Pediatric liver transplantation is a challenging technical exercise. Issues
include small recipient size, recipient and graft size mismatch, associated anatomical anomalies
and the need for meticulous surgical techniques and peri-operative care. Children with BA can
have associated congenital anomalies like BASM. A careful review of pre-operative imaging will
help in identifying most of these instances so that the surgeon is prepared and has a plan in
place to deal with these issues. Modifications to implantation techniques are usually necessary
with the need for additional vascular grafts in these children [50,51]. This has the potential to
increase post-operative morbidity [52,53].

Type of liver graft

The source of liver grafts in transplantation can be cadaveric donors or living donors. Whole
grafts from pediatric donors are uncommon. In the West, liver grafts for children are usually
obtained by splitting healthy livers from cadaveric adult donors. In developing countries, most
pediatric liver transplantations performed are split left lateral segment (LLS) grafts from living
donors; cadaveric donor living transplantation is much less common. This is because of low
deceased donor numbers and the shortage of technical skills to undertake split liver
transplantation. Additional concerns regarding the quality of deceased donor organs and
prolonged cold ischemia times also prevent using split liver techniques more consistently.
However in experienced units, split liver transplantations are excellent means of improving
access of small children for deceased donor grafts. The choice of transplant in these countries
ultimately depends on whether the child has a suitable family donor. If so, the transplant can be
completed in a timely fashion with good results. The alternative is a prolonged wait for a good
quality ‘splittable’ graft becoming available from a deceased donor.

Mismatch between recipient weight and graft size is a problem in transplantation of children less
than 10 kg. This is further accentuated when the recipient weight is less than 5 kg. The usual
left lateral graft averages around 250 grams. This gives a Graft Recipient Weight Ratio (GRWR)
of over five. In such relatively large grafts, there is a risk of portal hypoperfusion, vascular
complications, and graft ischemia/necrosis. Post-operative recovery is also affected due to
abdominal compartment syndrome requiring prolonged ventilatory support. Further graft
reduction is essential in these cases to reduce the GRWR to less than four. This can be carried
out by lateral reduction to decrease the graft volume, the use of segmental grafts, or non-
anatomical thinning for both volume and thickness [54,55]. There should be no hesitation in
delayed closure of the abdominal wall to prevent abdominal compartment syndrome.

Children with BA who have previously undergone KPE usually have significant intra-abdominal
adhesions. The adhesions are usually vascularized and adhesiolysis in this setting is associated
with risk of bleeding and enteric injury. Meticulous care should be taken during recipient
hepatectomy to avoid injury to the bowel during adhesiolysis. All serosal or full thickness
injuries should be repaired immediately so that they are not missed later in the operation.
Bowel perforation and peritonitis in children undergoing liver transplantation after KPE is quite
common, and a high index of suspicion should be maintained for any unexplained change in
clinical course of these children. When in doubt, it is safer to re-explore these children than
persist with conservative management until frank signs of peritonitis appear [56].

Portal vein complications

BA is associated with hypoplasia of the portal vein. The etiology of the portal vein hypoplasia is
multifactorial and could be related to the early onset hepatic fibrosis in these children which
prevents the usual development of the portal vein. Portal vein management in liver
transplantation depends on the severity of hypoplasia. In mild cases where portal flow is
adequate, a patch can be created using the portal vein bifurcation to anastomose to the donor
portal vein (branch-patch technique). Satisfactory flow should be documented with an intra-
operative Doppler in these cases. In cases where the portal vein diameter is less than 4 mm, it
is safer to use an interposition vein graft between the splenomesenteric vein junction and the
graft portal vein. The splenomesenteric vein junction is usually of good size because of the
continuous shunting that occurs across this junction.

In children with portal agenesis or a severely atretic portomesenteric system, the options are
limited. Meticulous dissection of the root of mesentery can sometimes identify a good quality
branch of super mesenteric vein with satisfactory flow. If available, a jump graft may be used
for ensuring portal inflow to the graft. When such a vein is not available, portocaval
hemitransposition may be a salvage option. Here the infrahepatic cava is used as portal inflow
by creating an end–to-end anastamosis between the infrahepatic cava and the graft portal vein.
This technique, first reported by Tzakis, et al. [57], has since been reported by several others in
the pediatric liver transplantation setting either as a primary procedure or as a salvage
technique in the re-transplant setting. The procedure is associated with significant early
morbidity in terms of pedal edema, renal dysfunction and ascites which usually resolves over
time. Lipshutz, et al. [58] reported a higher risk of primary non function with this technique,
especially when a split graft was used, and suggested that it could be due to high portal flow
causing a relative small for size syndrome in these children.

Post-transplant portal vein complications in the form of portal vein thrombosis or portal stenosis
have been reported in approximately 15% of children. Risk factors include small age, low
weight, small caliber portal vein and emergency transplant [59]. Early portal vein thrombosis
presents with worsening coagulopathy and hyperammonemia, and requires immediate surgical
exploration. Serial ultrasound Doppler scans (twice daily for the first three post-operative days
followed by once daily in the first week) will help in early diagnosis. Late portal vein stenosis is
usually diagnosed on routine Doppler ultrasound. While mild stenosis can be conservatively
managed, significant stenotic lesions are best treated by stenting and anticoagulation.

Outcome

Liver transplantation for BA has a very good outcome. Most large series from the West have
shown patient and graft survival rates at 10 years of 81-86% and 71-73%, respectively.
Previous KPE has not been associated with patient mortality in any of these studies [60-63].
Recent Indian studies have shown patient survival rates ranging from 70-90% [64,65]. At our
center, 144 pediatric liver transplants have been performed over the last 5 years. Of these, 65
(45.1%) were performed for biliary atresia with 90% patient survival rate. Studies have also
shown growth failure to be predictive for patient death and hence suggest a significant role for
nutritional support and early consideration of liver transplantation before nutritional and growth
failure occurs [60,66].

Role of primary liver transplantation

Liver transplantation as the primary modality of treatment for BA is a contentious issue [67].
Liver transplantation is a major surgery, is expensive, and submits the child to lifelong
immunosuppression. According to a recent study on the health status of children alive 10 years
after liver transplant, only 32% achieved an "ideal profile" as defined by first allograft, stable on
monotherapy, normal growth and absence of common immunosuppression-induced sequelae.
Impaired growth was seen in 23%, renal dysfunction in 9%, and post-transplant
lymphoproliferative disease (PTLD) in 5%. These patients also had a lower health-related quality
of life score than matched healthy children [68].

A successful KPE can avoid transplantation in upto one-third of children. In a large proportion of
children, it delays the need for liver transplantation thereby delaying the need for
immunosuppression. Clearance of jaundice after KPE provides an opportunity to improve the
nutritional status of the child. It will also give the family an opportunity to come to terms with
the need for transplant and the associated financial implications. Even if a transplant is required
at an older age, it is safer because the risk of technical complications is lesser, and the risk of
mortality is lower than in infancy [60,63]. The only indication for primary liver transplantation
for BA is in children who have synthetic liver dysfunction and features of portal hypertension. In
these children, a KPE will lead to liver decompensation.

The cost of liver transplantation for most families in developing countries is prohibitive. The cost
factor also favours KPE over primary liver transplantation in children with BA.

Conclusions

Inclusion of stool color cards as part of a screening program in the neonatal period will greatly
improve early detection of BA. Outcomes will improve if it is diagnosed at the earliest after
birth, and the child is referred to an experienced pediatric hepatobiliary unit for evaluation and
early KPE. If an early KPE is performed, nearly half of all children will reach teenage years with
their own livers, and about a third will have a truly long-term, symptom-free life with normal
liver biochemistry. Following KPE, liver transplantation is indicated in children in whom the KPE
fails or in those who develop portal hypertension and recurrent cholangitis despite a successful
KPE. Children with BA need a primary liver transplantation only if the diagnosis has been missed
in early infancy, resulting in liver failure. Sequential treatment combining KPE as first-line and
liver transplantation as second-line results in 90% survival for children with BA.

Contributors: PR: Content contribution and drafting; MS: Editing, drafting and literature search;
MSR: Content contribution; MR: Content supervision, drafting and editing.

Funding: None; Competing interests: None stated.

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The United Kingdom Restricts


Surgery for Biliary Atresia
Kelly, Deirdre MD, FRCP, FRCPI
Section Editor(s): Sherman, Philip M. M.D., F.R.C.P.C.; Büller, Hans M.D.

Journal of Pediatric Gastroenterology and Nutrition: November 1999 - Volume


29 - Issue 5 - p 529
News And Views

 Author Information
Surgical treatment for biliary atresia was developed in Japan by Professor M. Kasai in 1968. The
success of this palliative operation, the Kasai procedure, is dependent on many factors, including age at
surgery and experience of the surgeon. A British survey (BMJ 1985;290:347-7), reported that the Kasai
procedure took place in 16 centres in Britain between 1980 to 1982. They demonstrated that the initial
success of this operation, as defined as normalisation of plasma bilirubin, was related not only to age at
surgery but to surgical expertise. Their data demonstrated that only centres operating on more than five
cases per year had success rates in excess of 50%.
Following the publication of this study, the British Department of Health (DOH) advised that surgery
for biliary atresia should only be performed at King's College Hospital, London, and The Children's
Hospital, Birmingham, where there were established, centrally funded paediatric liver units.
Unfortunately, this advice was not heeded and paediatric surgeons continued to carry out biliary atresia
surgery locally, leading the DOH to reverse their decision in 1993.
A prospective survey designed to evaluate the incidence and long-term outcome of biliary atresia in the
British Isles between 1993 and 1995 (McKiernan et al., 1999; in press), found that 10 years later,
surgery for biliary atresia was still performed at 15 centres throughout the British Isles. Furthermore,
not only was the initial success of the procedure affected but overall survival with or without liver
transplantation also was clearly related to the caseload and experience of the centre. Essentially,
children who were operated on at more experienced hospitals were four times more likely to survive
without liver transplantation than those who were in less-experienced centres.
These data were made available to the DOH in 1997, which sought professional advice from the Royal
Colleges of Medicine and Surgery. Regrettably these professional bodies, which included the British
Association of Paediatric Surgeons, initially rejected the proposal to restrict the number of centres,
preventing the DOH from reinstating designation of the Kasai procedure to specialised centres only.
Following pressure from paediatric hepatologists, a Parents Support Group, The Children's Liver
Disease Foundation, and a media campaign that highlighted the national variation in success rates, the
DOH successfully achieved agreement among the relevant parties to restrict biliary atresia surgery to
three centres as of April 1999. These centres include King's College Hospital and The Birmingham
Children's Hospital as stated previously. A third centre, St. Jame's Hospital, Leeds, will be developed
to provide biliary atresia surgery, specialised liver services, and liver transplantation in due course as it
was thought important that all children with biliary atresia should have equal access to specialised care.
This time the DOH proposal has the support not only of the Royal College of Surgeons but also of the
British Association of Paediatric Surgeons, which has appointed Professor Lewis Spitz of Great
Ormond Street Hospital to audit the outcome of the surgery carried out at the three centres.
It is a sad reflection of today's world that the power of the media is needed to make sensible decisions
about medical and surgical services, but let us hope that this enlightened approach will indeed improve
survival for children with biliary atresia.
Deirdre Kelly, MD, FRCP, FRCPI
The Liver Unit; Birmingham Children's Hospital; Birmingham