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ORIGINAL ARTICLE
Year : 2012  |  Volume : 17  |  Issue : 4  |  Page : 147-152
 

Extrahepatic biliary atresia: Correlation of histopathology and liver function tests with surgical outcomes


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

Date of Web Publication13-Oct-2012

Correspondence Address:
Veereshwar Bhatnagar
Professor and Head, Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi-110029
India
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DOI: 10.4103/0971-9261.102326

PMID: 23243365

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   Abstract 

Aims: To correlate the age at surgery, liver function tests, and hepatic and portal tract histo-pathological changes with surgical outcome in the form of disappearance of jaundice in extrahepatic biliary atresia (EHBA). Materials and Methods : This is a retrospective study of 39 cases of EHBA. There were 19 males and 10 females. Kasai's portoenterostomy (KPE) along with liver biopsy was performed in these patients; for purpose of correlation this biopsy was considered to be the preoperative biopsy. These patients were divided into three groups based upon surgical outcome: (A) disappearance of jaundice; (B) initial disappearance of jaundice with recurrence after 3 months; and (C) persistence of jaundice. Postoperatively, liver function tests and liver biopsies were repeated at 3 months after the KPE. Results : There were 11 patients in group A (28%), 21 patients in group B (54%), and seven patients in group C (18%). The age at surgery was comparable in all the three groups. The postoperative levels of serum bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGTP) showed statistically significant improvement as compared with the preoperative levels in group A and B patients. Patients belonging to group C showed no improvement in the liver functions following surgery. The preoperative hepatic histopathological changes (hepatocellular alteration, cholestasis, bile ductular proliferation, and bile duct inflammation) showed a significant difference among the three groups; patients with lesser degrees of pre-existing histopathological changes had better outcome following surgery. Fibrosis was seen in all the three groups preoperatively but the difference was not statistically significant. Group C had significant fibrosis in more than 50% patients. Additional findings, viz. ductal plate malformation (9 patients, 23%) and giant cell transformation (19 patients, 49%) did not show any correlation with surgical outcomes. Conclusions : The liver function tests and the histopathological features appeared to affect the final surgical outcome of these patients. Higher degree of cholestasis, hepatocellular alteration, bile ductule proliferation, bile duct inflammation showed definite correlation with poor surgical outcome. High grade hepatic fibrosis and portal edema showed a trend towards poor outcome but did not achieve statistical significance.


Keywords: Extrahepatic biliary atresia, Kasai′s portoenterostomy, liver function tests, liver histopathology, results of surgery


How to cite this article:
Gupta L, Gupta SD, Bhatnagar V. Extrahepatic biliary atresia: Correlation of histopathology and liver function tests with surgical outcomes. J Indian Assoc Pediatr Surg 2012;17:147-52

How to cite this URL:
Gupta L, Gupta SD, Bhatnagar V. Extrahepatic biliary atresia: Correlation of histopathology and liver function tests with surgical outcomes. J Indian Assoc Pediatr Surg [serial online] 2012 [cited 2014 Apr 24];17:147-52. Available from: http://www.jiaps.com/text.asp?2012/17/4/147/102326



   Introduction Top


Extra hepatic biliary atresia (EHBA) remains one of the most serious diseases affecting infants and it has a fatal outcome if left untreated. [1] Kasai's portoenterostomy (KPE) has been the primary treatment of choice for EHBA since its introduction in 1959. The purpose of this study was to correlate the age at surgery, liver function tests and hepatic and portal tract histopathological changes with surgical outcome in the form of disappearance of jaundice.


   Materials and Methods Top


This is a retrospective study of 39 cases of EHBA treated by single pediatric surgeon (VB) between January 2007 and July 2009. There were 29 males and 10 females. The diagnosis of EHBA was confirmed based on standard clinical, biochemical, radiologic, radioisotope biliary excretion scan, histological, and operative findings. Kasai's portoenterostomy (KPE) along with the liver biopsy was performed in these patients; for purpose of correlation the liver biopsy taken at the time of KPE, was considered to be the preoperative biopsy. At the time of KPE, the age of the patients ranged between 60 and 120 (81.9±18.6) days; 32 patients (82.05%) were between 60 and 90 days and 7 patients (17.95%) were older than 90 days. The patients were divided into 3 groups based upon surgical outcome: A- disappearance of jaundice; B-initial disappearance of jaundice with recurrence after 3 months; and C- persistence of jaundice. The histopathological slides of the liver biopsy and the portal tract were reviewed by a single pathologist (SDG) (blinded for the results) and graded with uniform scoring. The slides were stained with hematoxylin and eosin (H and E). Six variables of liver histology, i.e, hepatocyte alteration, cholestasis, bile ductule proliferation, bile duct edema, inflammation, and fibrosis and two variables of porta, i.e, portal tract inflammation and fibrosis were evaluated using a semi quantitative scoring system. These features were graded as 0 signifying absent feature while 1, 2, and 3 reflected increasing intensity of the feature but fibrosis was graded as 0 = no fibrosis; 1 = mild portal fibrosis; 2 = porto-septal; non bridging fibrosis; 3 = bridging fibrosis; and 4 = cirrhosis. [2] Postoperatively, liver function tests and liver biopsy were done three months after the KPE. These were compared with the preoperative values to determine the change in the postoperative period and correlate the change with the surgical outcome groups.

Statistical analysis was carried out using STATA 9.0 (College Station, Texas, USA). Data were presented as number, percentage or median (range) as appropriate. The change in pre and postoperative values of continuous parameters were tested using Wilcoxon Signed Rank test and Categorical variables were tested using McNemar's Test. A P value <0.05 was considered statistically significant.


   Results Top


The mean age at KPE was not statistically different in groups A, B and C; it was 85.9±21.3 (n=11), 77.1±15.9 (n=21) and 90.0±21.2 days (n=7), respectively (P=0.211). The changes in serum bilirubin, alkaline phosphatase, and gamma glutamyl transpeptidase (GGTP) are summarized in [Table 1]. All these three parameters showed statistically significant improvement in the postoperative period in patients belonging to groups A and B. Patients belonging to group C showed no improvement in the liver functions following surgery.
Table 1: Pre- and postoperative liver function parameters in extra hepatic biliary atresia patients in the three surgical outcome groups

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Of the 39 children, postoperative liver biopsy was done in 31 children; 2 patients were lost to follow up and 6 patients expired in the postoperative period (3 from group C and 3 from group B). Of the 31 patients in whom a postoperative liver biopsy was performed, the tissue was not adequate for evaluation in 4 patients. The changes in preoperative and postoperative hepatic histo-pathological variables in 27 patients are summarized in [Table 2].
Table 2: Pre- and postoperative hepatic histopathological changes in the three surgical outcome groups of extra hepatic biliary atresia patients

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Four variables of liver biopsies i.e. hepatocellular alteration, cholestasis, bile ductular proliferation and bile duct inflammation showed a statistically significant difference in scoring among all these three groups in both preoperative and postoperative period. However, when postoperative histopathology was compared to preoperative, there was a general trend towards improvement in the scores of these histopathological variables in group A and less in group B. But the difference in scoring of these variables among each group was not statistically significant.

Bile duct edema did not show much difference in scores among three groups in both preoperative and postoperative liver histology. Fibrosis was present in all the three groups although grades were worse in group C (more than 50% patients showed grade 4). This difference was however, not statistically significant among the three groups. This might be due to lesser number of patients in group C. Also there was no statistically significant improvement in fibrosis following surgery in any of the three groups. However, fibrosis showed a general trend towards improvement in group A.

At the porta, portal tract inflammation and fibrosis did not show statistically significant difference in scores among three groups. Bile lakes were also seen in five patients [Figure 1], [Figure 2], [Figure 3], [Figure 4]. Additional findings noted in the 39 infants were ductal plate malformation (9 patients, 23%) and giant cell transformation (19 patients, 49%).
Figure 1: Photomicrograph shows ballooning as well as feathery degeneration of the hepatocytes with giant cell transformation, compression of hepatic sinusoids, and intracytoplasmic cholestasis [H and E, ×400]

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Figure 2: Section of the liver shows large areas of bile lake formation, surrounding by histiocytes, fibrosis and regenerating hepatocytes [H and E, ×40]

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Figure 3: Photomicrographs from a treatment naive extrahepatic biliary obstruction, show formation of hepatic nodules by markedly thickened intercommunicating portal tracts with fibrosis, inflammation and bile ductular proliferation (a) [H and E, ×40]. Higher power photomicrograph of the portal tracts show marked bile ductular proliferation with intra-ductular cholestasis, portal tract fibrosis and chronic inflammatory cell infiltrate (b) [H and E, ×200]. Post-surgery the liver biopsy of the same patient shows only mild enlargement, fibrosis of the portal tracts along with mild bile ductular proliferation (c) [H and E, ×40]. Post-surgery the portal tracts though show moderate fibrosis and chronic inflammatory cell infiltrate; there is a significant grade of reduction of bile ductular proliferation and intra-ductular cholestasis (d) [H and E, ×200]

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Figure 4: Photomicrograph of a liver biopsy with extra-hepatic biliary obstruction, shows formation of hepatic nodules, marked bile ductular proliferation, intra-ductular cholestasis with ductal plate malformation [H and E, ×40]

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   Discussion Top


The survival of infants with EHBA has improved significantly during the past two decades as a result of refinements in the KPE procedure complemented by advances in liver transplantation. The age at surgery, cholestasis, hepatocellular alteration, bile ductular proliferation, bile duct edema, inflammation, fibrosis, portal edema, inflammation, and ductal plate malformation have all been postulated to be of possible prognostic significance in various studies. We examined these factors in our 39 patients who had undergone KPE. Of the thirty-nine patients in this study, 29 were males and 10 were females. This ratio is in contrast to various studies which have reported that EHBA occurs more commonly in females as compared to males. [3],[4],[5]

Age at surgery

Advanced age at the time of surgery is thought to have a detrimental effect on the post-Kasai prognosis. [6],[7],[8],[9],[10],[11] In our study, the mean age at surgery was 81.9±18.6 days and no child was younger than 60 days. The mean age for the three surgical outcome groups, groups A, B, and C, was 85.9±21.3 (n=11), 77.1±15.9 (n=21), and 90.0±21.2 days (n=7), respectively (P=0.211). Thus the age at surgery was comparable in all the three groups, thereby implying that age at surgery did not have any significant influence on the clearance of jaundice. Nio et al. [12] 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. Similar findings were noted in other studies also, [13],[14] Moreover, a considerable percentage of patients who undergo late portoenterostomy (after 90 days of life) survived with their native livers for 5 and 10 years. [15],[16] Our findings were in contrast to those of Altman et al., [17] who found improved prognosis in children younger than 49 days and 50-70 days age groups as compared to children older than 70 days age. Also, most of other studies proved that higher age at surgery had been constantly linked with worse prognosis. [7],[18] In the report of a consensus meeting in India in 1998, the average age of presentation at a specialized center was shown to be 3.5 months. Even after reporting to large referral hospitals, lack of requisite diagnostic facilities and inadequate expertise in handling such cases further added to the delay which eventually deprived these infants of an opportunity of utilizing the currently available therapeutic modalities. [19]

Liver function tests

The serum bilirubin levels showed statistically significant improvement in the postoperative period in patients belonging to groups A and B. Similar improvement was seen in serum alkaline phosphatase and GGTP levels. This objectively reflected the better clinical outcome following surgery in patients belonging to groups A and B. Patients belonging to group C showed no improvement in the liver functions following surgery which implied that they were already in advanced stages of liver damage.

Clinical outcome and histopathological changes

The hepatic histopathological examination in EHBA is classically characterized by ductular proliferation, canalicular and cellular biliary stasis, swelling and vacuolization of biliary epithelial cells, portal tract edema and fibrosis, monocytic inflammatory cell infiltration of portal tracts and ductal plate malformation. [20] The severity of intrahepatic biliary cholangiopathy and the extent of hepatocyte injury are important determinants of prognosis. [21],[22],[23],[24],[25],[26] In our study, the hepatic histopathological changes (hepatocellular alteration, cholestasis, bile ductular proliferation and inflammation) in the preoperative biopsies showed a significant difference among the three groups thereby implying that the patients with lesser degree of hepatic damage were likely to have better outcome following surgery. Postoperatively also, these hepatic histo-pathological changes among the three groups were statistically significant. However, the postoperative biopsies did not show any statistically significant improvement from the preoperative status in all these groups. However, there was a general trend towards improvement in the patients belonging to group A. Larger series may demonstrate statistically significant improvement in patients having better postoperative outcome. Bile duct edema did not show any preoperative and postoperative difference between the three groups.

Fibrosis was seen in all the three groups preoperatively but the difference was not statistically significant among the three groups. Group C however had fibrosis in more than 50% patients. The lack of statistical significance might be due to small number of patients in this group. There was no statistically significant improvement following surgery in any of the three groups. However in our study, fibrosis showed a trend towards improvement in group A. The presence of cirrhosis in the liver periphery did not imply surgical failure because regenerative hilar nodules containing patent bile ducts can sustain an adequate bile flow. [27] Increased fibrosis compromises the flow of bile leading to jaundice and poor outcome even after surgery. Landing et al. had shown that ductal proliferation increased to peak at 205 days followed by regression by 400 days, in untreated patients, but the level of connective tissue continued to increase slowly and progressively and later became unresponsive to treatment. [28]

Ductal plate malformation (DPM) has been described in EHBA in many studies with an incidence varying from 21% to 63%. [29] In our study, ductal plate malformation in liver biopsy was seen in nine (23%) patients. One (0.9%) of 11 patients from group A, 4 (19.04%) of 21 patients from group B, and 4 (57.14%) of 7 patients from group C showed ductal plate malformation and from this it was evident that patients with DPM had poor outcome after KPE. Giant cell transformation was seen in 19 (49%) patients but did not seem to affect the surgical outcome.


   Conclusions Top


From this study, it appears that age at surgery may not be as significant a factor as has been made out in the past with regard to the surgical outcome. The liver function tests and the histopathological features were found to have a better correlation with the surgical outcome. Higher degrees of cholestasis, hepatocellular alteration, bile ductule proliferation, and portal edema showed definite correlation with poor surgical outcome. Similarly higher grades of fibrosis showed a trend towards poorer prognosis although it did not achieve a statistical significance. Nevertheless, even in the children belonging to group A, who showed good surgical outcome following surgery, liver histology showed residual abnormalities especially fibrotic changes. We suggest that the guiding principle for prognostication should be the liver histology rather than the age of the patient. This implies that surgery should still be offered to patients who are beyond the currently accepted age of 90 days as the cut off for prognosis in EHBA provided the liver histology shows lesser degrees of liver damage. Further prospective studies with larger number of patients and longer follow up will lend greater insight into the prognostic significance of hepatic histological changes in EHBA patients.

 
   References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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  [Table 1], [Table 2]


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