Biliary Atresiaโรคทางเดินน้ําดีตนั

Paisarn Vejchapipat, et al.

Department of Surgery, Faculty of MedicineChulalongkorn University, Thailand

Disclosure

None

Background

• Biliary atresia (BA) is characterized by inflammatory obstructive cholangiopathy of unknown origin, occurring in the perinatal period

• BA is the main cause of cholestatic jaundice in neonates with the incidence of 1:5,000-15,000

• If left untreated, the condition will lead to cirrhosis and death within the first two years

• BA is the most common ‘surgical’ cause of jaundice in infancy

• Surgical treatment usually involves two steps – Kasai operation (hepatic porto-enterostomy)

performed in infants– Subsequent liver transplantation if needed

• BA is the main indication for liver transplantation in infants and children

Background

Thailand

• Statistics in 2014

• Population: ≈66 million

• Pediatric: ≈12 million

• Births: ≈700,000 /year

Department of Provincial AdministrationMinistry of Interior

Etiology

• The etiology remains unsolved

• There are several hypotheses including– Occult viral infections– Immune-mediated injury– Maternal microchimerism– Ductal plate malformation– Pancreatico-biliary maljunction

Pathology• Various stages of inflammation causing progressive

destruction of the bile duct both intra- and extrahepatic

• Portal fibrosis and bile duct proliferation are pathognomonic

Hepatic iNOS Expression in BA

• Strong hepatic iNOS expression in BA patients• In BA, hepatocyte is likely to be the major source of

nitric oxide production

Vejchapipat P, et al. Hepatol Res 2008

Morphological Classification

95%

5%

Phenotypic classification

• Isolated BA

• Cystic BA (10%)

• CMV associated BA (10%)

• BA splenic malformation (BASM) syndrome

Davenport M. Neonatal Surgery 2018

Cystic BA

Report of Cystic Biliary Atresia

An unusual type of Biliary AtresiaSookpotarom P, Vejchapipat P. Eur J Pediatr Surg 2007

Effect of cystic change in BA

Davenport M. Diseases of the Liver and Biliary System in Children 2017

Recognized anomalies in the BASM syndrome

Davenport M, et al. Surgery of the Liver, Bile Ducts and Pancreas in Children 2017

True survival in BA and other anomalies versus isolated BA

Davenport M. Diseases of the Liver and Biliary System in Children 2017

Clinical Presentation

• Jaundice, acholic stools, dark urine and hepatomegaly

Diagnosis

• Symptoms and signs

• Conjugated hyperbilirubinemia

• Ultrasonography

• Hepatobiliary scintigraphy

• Intra-operative cholangiography

U/S: Triangular cord sign

The diagnosis of BA

• Babies (0-4 months old) with cholestatic jaundice and persistent acholic stools

Ultrasound

Triangular cord sign +ve IOC

Triangular cord sign –ve

IOC (age> 60days)

DISIDA (age <60days)

Choledochalcyst Surgery

Intra-operative Cholangiography

Biliary Atresia Non-BA

IOC of BA

• Most of the BA patients (95%) had atresia at portahepatis (type III)

• BA type III with patent cystic duct and common bile duct were found 23% in our series

Treatment

Prof. Morio Kasai Hepatic Portoenterostomy 1955

Kasai operation

J Pediatr Surg 2012;47:1023-7

Kasai M. J Pediatr Surg 1968

Kasai operation

Operative Findings

Small gall bladderCholestatic liver

Hepatic Portoenterostomy (Kasai Operation)

Dissection of Porta Hepatis

Small GB

Round ligament

Hepatic artery

Portal vein

Enlarged LN

GB fossa

Hepatic Portoenterostomy (Kasai Operation)

Hepatic Portoenterostomy(Kasai Operation)

Outcome of Kasai operation

• Good outcome (40-60%)– Jaundice-free, yellow stool, TB < 2 mg%– Survival > 5 years

• Fair outcome (20-30%)– Decreased Jaundice, yellow stool, but TB > 2 mg%– Survival > 3 years

• Poor outcome (20-30%)– Increased Jaundice and signs of chronic liver disease– Survival < 3years

Grosfeld et al. Surgery 1989

Prof. Mark Davenport (King’s College London)@ Annual Meeting of Royal College of Surgeons of Thailand 2009

Davenport M, et al. Surgery of the Liver, Bile Ducts and Pancreas in Children 2017

59

True and native liver survival curves for BA (n=443) in England and Wales (1999–2009)

Diseases of the Liver and Biliary System in Children 2017

Factors Affecting The Outcome

• The age at the time of operation

• The status of the liver

• Phenotypic classification

• The size of bile canaliculi at porta hepatis

• Surgeons’ experience

• Patient load per year at that centre

Effect of age at Kasai operation

Davenport M, et al. Surgery of the Liver, Bile Ducts and Pancreas in Children 2017

CMV-associated BA vs. native liver survival

Complications

• Ascending cholangitis (30-60%)

• Portal hypertension (34-76%)

• Hepato-pulmonary syndrome

• Intrahepatic biliary cysts

Chulalongkorn’s Experience• 1986-1995:

– 115 cases– Chula Med J 1996

• 1996-2001:– 92 cases– Asian J Surg 2005

• 2002-2005:– 53 cases– J Pediatr Surg 2007

• 2006-2014:– 89 cases– Pediatr Surg Int 2016 Chulalongkorn University

Age at The Time of Surgery

AGE

210.0200.0

190.0180.0

170.0160.0

150.0140.0

130.0120.0

110.0100.0

90.080.0

70.060.0

50.040.0

30.0

16

14

12

10

8

6

4

2

0

Std. Dev = 36.44 Mean = 90.3N = 92.00

(days)

No.

ofpa

tient

s

Only 23% had Kasai operation before 60 days of age63% operated before 90 days of ageMedian age of surgery = 88 days

Sookpotarom et al. Asian J Surg 2005

Cases/year

Clearance of jaundice within 6 months after Kasai Operation

38%

50.7%56.6% 58.3%

The Effects of Post-op Steroids

• The use of high-dose post-op steroids is controversial

• 53 BA patients over 4 years

• Steroids did not statistically improve early outcome in BA– Jaundice-free: 61% vs. 50% (steroid vs. non-steroid)

Vejchapipat P, et al. J Pediatr Surg 2007

The Effects of Post-op Steroids

Chusilp S, et al. Pediatr Surg Int 2016

1-year survival 85%3-year survival 70%5-year survival 65%

Chusilp S, et al. Pediatr Surg Int 2016

P=0.0215

Chusilp S, et al. Pediatr Surg Int 2016

Good outcome group Poor outcome group5-year survival 96% 36%

HR 0.05

95%CI 0.01-0.15

P <0.001

Chusilp S, et al. Pediatr Surg Int 2016

Circulating E-Selectin in Biliary Atresia

• Serum E-selectin of BA patients was higher than the controls

• There was an increase in serum E-selectin in BA patients with jaundice compared to those without jaundice

BA patients Controls0

100

200

BA, N=53Control, N=10

Seru

m s

E-se

lect

in(n

g/m

L)

P<0.01

Jaundice-free Jaundice0

100

200

Jaundice-free (N=32)Jaundice (N=21)

BA patientsSe

rum

sE-

sele

ctin

Mea

n+SD

(ng/

mL)

P=0.035

Vejchapipat P, et al. Eur J Pediatr Surg 2008

Serum TGF-β1 and EGF in BA

Vejchapipat P, et al. Eur J Pediatr Surg 2008

Good outcome Poor outcome0

50

100

Seru

m T

GF-β

1(n

g/m

l)

P=0.002

N=40 N=27

Good outcome Poor outcome0

50

100

150

200

250

Seru

m E

GF

(pg/

mL)

P=0.02

N=40 N=27

BA patients with good outcome had serum TGF-β1 and EGF higher than those with poor outcome

Systemic nitric oxide production was elevated in BA

Control BA0

50

100

Subjects

µ mol

/L (m

ean+

SD)

P=0.001

N=12 N=65

Vejchapipat P, et al. Pediatr Surg Int 2006

The fate of biliary atresiaBiliary atresia

Kasai operation

Transplantation

Poor outcome Good outcome

Short-term~40% ~60%

Deterioration Normal life

Long-term50% 50%

Roles of Liver Transplantation

• Patients with decompensated liver cirrhosis at the time of referral

• Patients without bile drainage after Kasai operation

• Patients with partial bile drainage with– Developmental retardation– Their sequelae become uncontrollable

• Primary liver transplantation is still controversial

Conclusions• Neonates or infants with direct hyperbilirubinemia

must be investigated to rule out biliary atresia

• Kasai operation is still the first therapeutic option for biliary atresia

• Liver transplantation is preserved for patients with failed Kasai or severe liver fibrosis

• Teamwork of healthcare providers is critical

THANK YOU