www.elsevier.com/locate/jpedsurg

Kasai portoenterostomy—new insights fromhepatic morphology

Ali Hussein, Judy Wyatt, Ashley Guthrie, Mark D. Stringer*

Department of Histopathology and Children’s Liver Unit, St James’s University Hospital, Leeds, LS9 7TF, UK

0022-3468/05/4002-0006$30.00/0 D 200

doi:10.1016/j.jpedsurg.2004.10.018

Presented at the 51st Annual Congr

Paedriatic Surgeons, Oxford, England, J

* Corresponding author. Tel.: +44 0

6691.

E-mail address: mdstringer@dial.pip

Index words:Biliary atresia;

Kasai portoenterostomy;

Liver transplantation

AbstractBackground/Purpose: The aim of this paper was to investigate the mechanism of long-term biliary

drainage after Kasai portoenterostomy by clinicopathologic study of hepatic morphology in explanted

livers.

Methods: Explanted livers from 13 consecutive children undergoing transplantation for biliary atresia

were examined in detail using a standardized protocol. Group 1 (n = 6) had no Kasai procedure before

transplantation at a median age of 8 m. Group 2 (n = 4) were transplanted at a median age of 10 m after a

failed Kasai portoenterostomy. Group 3 (n = 3) had a successful Kasai but required transplantation for

complications of chronic liver disease at 12-14 years. Pathology findings were correlated with hepatic

morphology determined by pretransplant magnetic resonance imaging.

Results: Large perihilar regenerative nodules (8-14 cm diameter) were observed in 2 patients after

successful Kasai portoenterostomy, less well-defined perihilar nodules in group 2 patients, and no

regenerative nodules in group 1. Microscopically, group 1 had diffuse biliary cirrhosis with evidence of

progressive ductopenia during infancy. In group 2, perihilar regenerative nodules showed variable portal

fibrosis but no cirrhosis and bile ducts were present with 68%-100% of hepatic arteries; in peripheral

cirrhotic areas, bile ducts were absent in patients older than 9 m. The perihilar regenerative nodules in

group 3 patients had a noncirrhotic architecture with preserved bile ducts, but the peripheral parenchyma

was cirrhotic; one patient had diffuse macronodular cirrhosis. These morphologic findings correlated

well with magnetic resonance images, highlighting the preservation of relatively normal perihilar liver

architecture after successful Kasai portoenterostomy.

Conclusions: Unoperated biliary atresia is associated with progressive intrahepatic ductopenia leading todiffuse biliary cirrhosis. Kasai portoenterostomy can result in the growth of large perihilar regenerative

nodules, probably as a consequence of surviving intrahepatic ducts in this region. In some patients, long-

term success after Kasai portoenterostomy may depend on hyperplasia of the perihilar liver.

D 2005 Elsevier Inc. All rights reserved.

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ess of the British Association of

uly 27-30, 2004.

113 206 6689; fax: +44 0113 206

ex.com (M.D. Stringer).

Biliary atresia (BA) is an obliterative cholangiopathy

with an incidence of about 1 in 16,000 live births [1]. It is

the commonest indication for pediatric liver transplantation.

In 1959, Kasai and Suzuki reported that portoenterostomy

Journal of Pediatric Surgery (2005) 40, 322–326

Kasai portoenterostomy—new insights from hepatic morphology 323

could result in effective bile drainage in infants with

previously untreatable BA [2]. The Kasai portoenterostomy

remains the standard operation for BA, achieving complete

clearance of jaundice in approximately 60% of affected

infants [3]. We investigated the mechanism of long-term

biliary drainage after portoenterostomy by a clinicopatho-

logic study of hepatic morphology in explanted livers from

patients undergoing liver transplantation for BA.

ig. 2 Hepatic histology from the liver shown in Fig. 1: (a)

entral hilar nodule showing well-preserved architecture and bile

ucts and (b) more peripheral cirrhotic liver (H&E).

1. Methods

Clinical and histologic data from 13 consecutive children

undergoing orthotopic liver transplantation (OLT) for BA,

between December 2000 and March 2004, were analyzed.

Group 1 (n = 6) were referred late (aged 5-13 months, n = 3)

or with advanced liver disease (n = 3) and had no Kasai

procedure before OLT at a median age of 8 (3-18) months.

Group 2 (n = 4) underwent Kasai portoenterostomy at less

than 8 weeks of age but failed to become anicteric; their

median age at OLT was 10 (7-13) months. Group 3 (n = 3)

consisted of 3 patients who had a successful Kasai but

required OLT at 12.3 (12-14) years of age because of

chronic liver disease and complications of portal hyperten-

sion in 2 (both anicteric) and chronic cholangitis in 1. All

Kasai portoenterostomies were in patients with type 3 BA

(completely obliterated extrahepatic bile ducts at porta

hepatis). Two children in group 1 and one in group 2 had

the biliary atresia splenic malformation syndrome.

Both the macroscopic and microscopic pathology of the

explanted liver were reviewed by 2 pathologists. Standard

histology blocks were taken from the right lobe, the left

lobe, the caudate lobe, the region of the portoenterostomy,

and from any unusual macroscopic areas within the liver,

including nodules (12-14 blocks per case). Specimens were

stained with hematoxylin and eosin, and the extent and

distribution of fibrosis/cirrhosis was assessed. Portal areas

Fig. 1 Macroscopic appearance of explanted liver showing large

central nodules surrounded by cirrhotic liver (centimeter scale).

Fc

d

were assessed for the presence of bile ducts accompanying

branches of the hepatic artery. These bile ducts were

carefully differentiated from the ductular proliferation

associated with biliary cirrhosis. The percentage of portal

tracts with bile ducts accompanying hepatic arteries was

calculated for cirrhotic and noncirrhotic areas.

The pretransplant magnetic resonance images and

ultrasound scans from all patients were reviewed indepen-

dently by an experienced radiologist blinded to the

histologic findings. In particular, the architecture of the

liver parenchyma was assessed.

2. Results

Macroscopically, the livers from group 1 patients were

deeply bile stained and firm with a uniform appearance and

no regenerative nodules. Group 3 livers had a macronodular

appearance with a single (14 cm diameter) or multiple (up to

8 cm) central perihilar nodules in 2 cases (Fig. 1), and

diffuse macronodular cirrhosis in 1. Group 2 showed

intermediate features with small, less well-defined regener-

Fig. 3 Gradient echo T1 magnetic resonance image showing a

large central hilar nodule in a 14-year-old boy after Kasai porto-

enterostomy.

A. Hussein et al.324

ative nodules in the region of the caudate lobe and adjacent

to the portoenterostomy.

Microscopically, group 1 livers had diffuse biliary

cirrhosis. Portal edema, marked ductular proliferation with

frequent bile plugs, and giant cell transformation of

hepatocytes were noted, particularly in younger patients.

Less ductular proliferation was observed in older infants

with unoperated BA. Ductopenia developed with time:

intrahepatic bile ducts accompanied 62% of hepatic artery

branches at 3 months of age, 19% of arteries at 6 months,

and were absent in 3 patients aged 8, 11, and 18 months

at OLT.

Within the central regenerative nodular areas in the

group 2 livers, there was variable portal fibrosis but no

cirrhosis, and bile ducts were associated with 68%-100% of

Table 1 Summary of morphologic findings in explanted livers

Group Median age at

OLT (range)

Macroscopic

pathology

Histology

1 (unoperated)

(n = 6)

8 (3-18) m Uniform appearance,

no regenerative

nodules

Diffuse b

cirrhosis.

proliferat

infants

2 (failed Kasai)

(n = 4)

10 (7-13) m Small, less well-

defined regenerative

nodules in caudate

lobe and adjacent to

portoenterostomy

Variable f

no cirrho

regenerat

Periphera

3 (successful

Kasai)

(n = 3)

12 and 14 y Macronodular, large

central perihilar nodule

(s) (up to 14 cm

diameter)

Noncirrho

in regene

biliary cir

12 y Diffuse macronodular

cirrhosis

Cholangit

larger per

hepatic artery branches. In peripheral cirrhotic areas of

these livers, bile ducts were found accompanying 14% of

arterial branches in the liver removed at 7 months but in

none of the explanted livers from patients aged between 9

and 14 months.

In group 3 livers, bile ducts were present in 79% and

86% of portal areas within the large perihilar nodules of the

2 anicteric patients with complications from portal hyper-

tension (Fig. 2a); fewer ducts were found in the more

peripheral cirrhotic liver (6.6% in 1, variable in the other)

(Fig. 2b). One patient in group 3 had diffuse cirrhosis, with

active cholangitis affecting larger central, perihilar hepatic

ducts, and absence of most of the smaller ducts.

Hepatic architecture determined by magnetic resonance

imaging (MRI) before OLT correlated well with these

pathologic observations: group 1 showed diffuse parenchy-

mal changes; in group 2, 2 patients had relatively well-

preserved and homogeneous perihilar regions within segment

4 compared with the surrounding liver, and 2 had diffuse pa-

renchymal changes throughout the liver; in group 3, 2 patients

had large relatively homogeneous perihilar liver nodule(s)

centered on segment 4 seen on gradient echo T1 scans and on

dynamic gadolinium enhanced 3D gradient echo scans

(Fig. 3). The remaining patient in group 3 (with histologic

cholangitis) had larger central nodules which were relatively

homogeneous compared with the surrounding liver paren-

chyma, but these were much less well defined than the perihi-

lar nodule(s) seen in the other 2 patients in this group.

Ultrasound scans failed to demonstrate these architectural

changes.

The morphologic findings are summarized in Table 1.

Pretransplant alpha-fetoprotein levels were normal in all

patients.

% portal tracts

with bile duct

Magnetic

resonance–hepatic

morphology

iliary

Less ductular

ion in older

62% at 3 m, 19%

at 6 m, 0% after

8 m of age

Diffuse parenchymal

changes in all

ibrosis but

sis in perihilar

ive nodules

68%-100% Diffuse changes in 2,

relatively homoge-

neous perihilar

parenchyma in 2l areas cirrhotic 14% at 7 m, 0%

after 9 m of age

tic architecture

rative nodules,

rhosis peripherally

79% and 86%

within perihilar

nodules, much

fewer but variable

peripherally

Large homogeneous

perihilar nodule(s)

is in residual

ihilar ducts

0% outside perihilar

area

Poorly defined

relatively

homogeneous central

nodules

Kasai portoenterostomy—new insights from hepatic morphology 325

3. Discussion

The Kasai portoenterostomy continues to be the defin-

itive primary treatment for the vast majority of patients with

BA. Approximately 60% of infants treated within 3 months

of birth will completely clear their jaundice [3], and more

than half of these will remain healthy for the next 5-10 years

with their native liver [4]. However, even with effective bile

drainage, progressive liver fibrosis and cirrhosis are

frequent, and long-term survival in most patients is

dependent on liver transplantation [4]. The early natural

history of the pathology of unoperated BA is not well

documented, and the mechanism of successful biliary

drainage after Kasai portoenterostomy is only broadly

understood. This clinicopathologic study investigated the

morphology of explanted livers in 3 groups of patients

undergoing transplantation for BA: infants and older

children with unoperated BA aged between 3 and 18

months, a similar aged group of children in whom the Kasai

procedure was unsuccessful, and older patients with

complications of BA, including 2 anicteric children with

complicated portal hypertension.

Kasai et al showed that intrahepatic bile ducts at the porta

hepatis disappeared with increasing age, hence the need for

early portoenterostomy [5]. Ductopenia is well documented

in liver biopsies from patients with BA after Kasai

portoenterostomy. We have confirmed that in unoperated

BA, there is progressive intrahepatic ductopenia during

infancy leading to the development of diffuse biliary

cirrhosis. In our study, bile ducts accompanying branches

of the hepatic artery were absent from portal tracts of infants

aged 8 months or more. However, progressive intrahepatic

ductopenia is prevented in areas where biliary drainage is

achieved and may therefore be a consequence of obstruction

rather than an intrinsic feature of the pathogenesis of BA.

Our findings show that after Kasai portoenterostomy,

liver morphology and pathology are not necessarily

homogeneous. Two distinct regions may be present: a

perihilar regenerative noncirrhotic region (centered on

segment 4) and a more peripheral cirrhotic area. The central

region is functional and has near normal histology with bile

ducts accompanying most of the hepatic artery branches in

the portal tracts. These observations suggest that in some

patients the Kasai portoenterostomy may result in the

growth of perihilar regenerative nodule(s), probably as a

consequence of survival of intrahepatic ducts in this region

but not elsewhere. Long-term survival after Kasai may then

depend on the anatomical extent of perihilar hyperplasia and

the ability of this region to maintain liver function in the

presence of progression to cirrhosis in more peripheral parts

of the liver. In one study of children after portoenterostomy,

MRI scans showed that half had atrophy or fibrosis in either

one lobe of the liver or in the peripheral zone [6].

Other smaller studies have identified similar morphologic

findings in some patients after Kasai portoenterostomy.

Yeung et al reported 2 anicteric children with portal

hypertension who developed hepatic decompensation at 6

years of age and underwent OLT [7]. The hepatectomy

specimens showed a central zone of relatively normal

parenchyma and a peripheral zone of cirrhosis. Takahashi

et al reviewed 5 livers from patients aged between 5 and 23

years undergoing OLT for BA [8]. All explants showed a

hypertrophic perihilar region in segment 4 with near normal

bile ducts and atrophic, fibrotic areas with ductopenia more

peripherally. They postulated that portoenterostomy

achieves segmental bile drainage and is more likely to drain

the bile ducts from segments 4, 5, and 8 which are situated

medially and superiorly to the portal vein bifurcation. Ijiri et

al reviewed 10 post–Kasai hepatectomy specimens; a large

central regenerative nodule with relatively normal liver

architecture was found in 3 older children and a poorly

defined central hypertrophic area in another 2 [9]. None of

these studies included a control group of children with

unoperated BA. Inclusion of the latter demonstrates that

even after a failed Kasai procedure, the perihilar region of

the liver may show regenerative changes indicating that the

hyperplasia observed after successful portoenterostomy is

indeed caused by the portoenterostomy and not just a

consequence of BA.

These observations have clinical implications. Liver

histology may be variable within the liver in long-term

survivors of BA. Patients with a large central nodule may

have well-preserved liver function but suffer from compli-

cations of portal hypertension. As these patients can be

identified by MRI or computed tomography scan [9] (but

not by ultrasound), the possibility of portosystemic shunting

in those not responding to endoscopic therapy arises

(provided there are no contraindications such as chronic

encephalopathy which was present in one of our patients).

However, transplantation is currently our preferred option

because hepatic decompensation is known to occur in these

patients, either because the central hyperplastic nodules are

completely encased by cirrhotic liver and cannot expand to

keep pace with the demands of growth [7], or because

transitional areas between healthy central parenchyma and

peripheral cirrhotic liver gradually fail [8].

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