Imaging in biliary atresia (BA)

Abdominal ESPR Task force

Marcello NapolitanoV. Buzzi Children’s Hospital

Milano IT

Definition and epidemiology

• Inflammatory cholangiopathy of infancy with progressive fibrosis and obliteration of extrahepatic and intrahepatic bile ducts, resulting in biliary cirrhosis

• 1/5000-20000 live births worldwide

• At least 50 % of all pediatric liver transplantations

2 forms

• Perinatal form (80%) viral trigger and interactions between innate and adaptive immune responses

• Embryonic form (20%) Biliary Atresia Splenic Malformation (BASM)

•polysplenia•intestinal malrotation•preduodenal portal vein •absent inferior vena cava •aberrant hepatic artery•abdominal heterotaxia

• Cystic BA

Histology

• Intrahepatic bile ductular proliferation

• Bile duct and ductular bile plugs

• Portal or perilobular fibrosis

• Edema

• Preservation of the basic hepatic lobular architecture

Anatomical forms

2/3

(D Pariente, EMC 2013)

Treatment

• Kasai hepatoportoenterostomy

• Left untreated / failure of the Kasai procedure > biliary cirrhosis > end stage liver failure > death by 3 years of age

• if operated < day 60 = stabilization in 80%• if operated > day 90 = success rate only in 20%

• Transplantation if primary Kasai failed

• Early diagnosis is the real goal of imaging but is challenging!

Diagnosis

• Differentiation of BA from other nonsurgical causes of neonatal cholestasis is challenging

• GGT

• US

• MRCP

• Nuclear Medicine

• Percutaneous Biopsy

• Percutaneous cholecysto-cholangiography

Surgery is the only reference standard

Literature review

• PubMed database search (January 1999-December 1, 2018): (triangular cord or gallbladder or ultrasound or US) AND biliary atresia

• 599 relevant studies

• On the basis of title or abstract 46 papers were identified as relevant

• After full review 20 papers (file 1) fulfilled all inclusion criteria:– Studies that included more than 10 patients who underwent US to evaluate infantile

cholestasis– Surgery used as a reference standard for BA– Results were sufficient to evaluate the diagnostic performance of sonographic features in

patients with BA– Full texts in English– Only the most recent or complete study was used to avoid duplication of information

• 1906 patients age range 3-360 days– Limitation factor: The range of population age is very large: 3-360 days. Time matters!

Prenatal diagnosis

• Isolated prenatal non visualization of gallbladder: 3% probability of BA

• US markers of BA: heterotaxy, biliary cystic malformation

• If non visualization of the GB is associated with other disorders: 80 % of the fetuses have pathology (cystic fibrosis, BA…)

• MRI could show evocate the diagnosis of cystic BA (dd: choledochal cyst)

Antenatal imaging: choledocal cyst VS cystic BA –

percutaneous opacification

Prenatal diagnosis

Intrahepatic bile duct dilation observed in patients with choledochal cyst: difficult to see on prenatal images

GB with an irregular wall associated with a cyst of the extrahepatic biliary tractMorel B Clinical Case Reports 2015

Courtesy of P. Petit

Embryonic form

Azygos continuation - Polysplenia

• US Features suggestive of BA:-Triangular cord sign (TCS)-Gallbladder anomalies (GBA)-Hepatic subcapsular flow (HSF)-HA enlargement-Micro or macrocyst-Nonvisualization of CBD

• Exclude: -choledochal cyst (Intrahepatic bile duct dilation)-gall stones

No features are diagnostic for BA: a normal US does not rule out BA • (1A) JPGN 2017;64: 154–168

US postnatal is useful to demonstrate

• TC: obliterated fibrous ductal remnant

• Lee Radiology (2003): thickness of the echogenic anterior wall of the anterior branch of the right PV just distal to the right PV on a longitudinal image without including the right HA

• Other Authors consider TCS anterior to or near to the bifurcation of the PV measured both in trasverse or longitudinal scans

• TCS is usually reported positive if >3-4 mm

• Variability of TCS measure due to the position of measurement

• TCS is present in 17% of infants younger than 30 days and in 56% of the oldergroup (Hwang SM Eur Radiol)

BA is a progressive disease!

TCS

US feature n. of studies Sensitivity Specificity DOR

TCS 19 0.68 (0.57-0.78) 0.947 (0.92-0.97) 40.2 (20.8-70.8)

• Fasting time before US examination: at least 4 h

• Absence of a gallbladder

• GB length <15-19 mm

• Abnormal shape and wall of the gallbladder

• No contraction of the gallbladder after feeding

• If more than one type of GBA included, only the most used was adopted for calculating data

• GBA were common in both younger than 30 days and older BA group (Hwang SM Eur Radiol)

GBA

US feature n. of studies Sensitivity Specificity DOR

GBA 17 0.79 (0.70-0.86) 0.81 (0.73-0.86) 16.5 (8.1-30.1)

GB absence 4 0.2 (0.13-0.30) 0.98 (0.93-1) 17.5 (4.04-50.1)

GB lenght 4 0.71 (0.59-0.81) 0.79 (0.70-0.86) 10.1 (5.52-16.9)

GBA

Abnormal looking GB small and atreticPseudo GB

Non communicatinggallbladder –hyperechoic tract between the GB and the porta hepatis

Irregular wall GB

Courtesy of S. Franchi-Abella

Normal appearing GB – BA

A normal US does not rule out BA

Courtesy of P. Petit

HSF• Color Doppler US can be used to detect HSF in patients with BA; hyperplastic and

hypertrophic changes in branches of the HA are observed in patients with BA

• Problems of reproducibility according to the US platform, the probe, the Doppler andthe preset used

Male 3 months10 days old

sensitivity (range) 0.96-1

specificity (range) 0.86-0.97

No. ofStudies

3

HA diameter• Range of the diameters of the normal HA 1.0 –1.4 mm according to Kim

• HA diameter is larger in patients with BA (due to decrease portal flow secondary to cirrhosis)

• Enlargement of HA diameter (1.5 mm at the level of proximal right HA Kim and Mittal, 2.05 mm El Guindi) can be helpful in the US diagnosis of BA

• HA diameter was significantly smaller in BA group younger than 30 days (Hwang SM Eur Radiol)

US feature n. of studies Sensitivity Specificity DOR

HA enlargement 4 0.82 (0.71-0.89) 0.70 (0.51-0.84) 12.8 (3.05-36.1)

• Macrocyst are along the hilar pediculum: 0.5-4cm

• Visible on prenatal diagnosis

• ≠ choledocal cyst with intrahepatic bile duct dilation

• No bile duct dilatation in a patient with acholicstools = BA

Macrocyst

Courtesy of S. Franchi Abella

• Microcyst are at the site of the TCS that may be or not present, confluence of the bile ducts : 2-4 mm

• Not visible on prenatal diagnosis

• They can disappear during follow-up before surgery

• Color Doppler to differentiate cyst from curving vessels

Microcyst

Courtesy of S. Franchi Abella

Koob M Eur Radiol (2017) 27:1812–1821

US sign Sensitivity Specificity

Macrocyst 0.1 0.99

Microcyst 0.2 0.98

Macro or microcys

0.25 0.97

• The visibility of CBD whatever its diameter does not rule out a BA

• The difficulty is to see the whole extrahepaticbiliary tree from the right and left canal to the distal CBD

Nonvisualization of CBD

sensitivity (range) 0.93-0.95

specificity (range) 0.48-0.92

No. ofStudies

3

• Liver shear wave speed measurements are significantly higher in children with BA when compared to those with other causes of cholestatic jaundice in infants but not in the youngest infants less than 30 days

• Grey‐scale US has better diagnostic performance for BA than elastography. Elastography could improve diagnostic performance especially in infants > 30 days and for prognosis assessment (Dabadie ESPR 2018)

• Variability between manufacturer using different elastography technique and even more variability using different probes (linear vs convex) from the same manufacturer

• There is no cut off value to differentiate cirrhosis due to BA from others cirrhosis

• A normal elastography does not rule out BA

Elastography

sensitivity (range) 0.81-0.97

specificity (range) 0.67-1

No. ofStudies

2

Elastography

MRCP

• MRCP is not routinely recommended in infants with undiagnosed cholestasis by NASPGHAN

• Siles Pediatr Radiol (2014): the whole extrahepatic ducts are visible only in 62.5% of normal children less than 3 months old

sensitivity 89.7% (84.8%-93.4%)

specificity 64.7% (58.0%-71.0%)

LR+ 3.10 (1.59-6.06)

LR− 0.16 (0.06-0.44)

He World J Pediatr (2016)

MRCP meta-analysis

Limited specificity of MRCP, ERCP, PTCC provides a limited role in the general guidance to caregivers toward diagnosing BA in the present era (JPGN 2017;64: 154–168)

Nuclear Medicine

• Hepatobiliary scintigraphy is not routinely recommended by NASPGHAN for the evaluation of cholestatic jaundice in infants

• Preparation with Phenobarbital to activate liver excretory enzymes and increase bile flow

• Cholescintigraphic images should be acquired at multiple time up to 24 hours

24 hPersistent hepatogram and no biliary-to-bowel transit over 24 h

sensitivity 98.7% (98.1–99.2%)

specificity 70.4% (68.5–72.2%)

LR+ 3.01 (2.63–3.47)

LR− 0.07 (0.05–0.09)

DOR 55.8 (41.2–75.4)

Nuclear Medicine meta-analysis

Kianifar Pediatr Radiol (2013)

•Limited specificity precludes the use of the HBS scan as a standalone test in making a definitive diagnosis of BA (1B)(JPGN 2017;64: 154–168)

Percutaneous Biopsy

• Typical histological findings (bile duct proliferation, bile plugs, and fibrosis) in an appropriately timed liver biopsy is the most supportive test in the evaluation of the infant with protracted conjugated hyperbilirubinemia (1B). (JPGN 2017;64: 154–168)

• A percutaneous liver biopsy is recommended before performing a surgical procedure by NASPGHAN

• If the biopsy is done before 6 weeks of age, the biopsy may have to be repeated if the results are equivocal

• 50% - 99% of patients with BA are correctly identified with biopsy

• Complication rate 1.7-4.6%

Liver biopsy cannot exclude BA completely

Percutaneous cholecysto-cholangiography(PTCC)

• US guided

• GA vs sedation vs local lidocaine

• Antibiotic prophylaxis for percutaneous biliary procedures is recommended by the Society of Interventional Radiology guidelines

• 22-25 G needle

• Non ionic contrast medium (CEUS PTCC? Zhou L Radiology 2017; 000:1–7 https://doi.org/10.1148/radiol.2017170173)

• When noninvasive techniques fail PTCC should be done followed by liver biopsy when BA is ruled out

• Puncture of the gallbladder allows sample of bile for biochemical studies in suspected genetic cholestasis

PTCC

• Spatial resolution >> MRI

• PTCC useful to confirm or rule out BA in difficult cases

• dd: neonatal sclerosing cholangitis or hypoplastic intrahepatic bile ducts

sclerosing cholangitisNormal BA

Courtesy of S. Franchi-Abella

Radiology 2018; 00:1–9 https://doi.org/10.1148/radiol.2018172390

• Low-risk group: liver biopsy may be postponed• Intermediate-risk group: liver biopsy can be considered• High-risk group: prompt liver biopsy with or without

intraoperative cholangiography

Journal of Hepatology 2014 vol. 61 j 116–123

The total score ranged from 0 to 37.18 and a cut-off value of >23.927 could discriminate BA from other causes of neonatal cholestasis with sensitivity and specificity of 100% each

http://dx.doi.org/10.1016/j.dld.2014.07.104

Less enthusiastic results: global sensitivity was 31% (5/16), specificity 90.9% (10/11). Is this risk score reproducible?

GBA Napolitano ZhouAJR 2016; 206:W1–W10

Sensitivity 79%(70%-86%)

85%(76%–91%)

Specificity 81% (73%-86%)

92% (81%–97%)

DOR 16(8-30)

61(18–204)

TCS + GBA Napolitano ZhouAJR 2016; 206:W1–W10

Sensitivity 87%(51%-97%)

95% (70%–99%)

Specificity 90%(68%-97%)

89% (79%–94%)

DOR 99 (8-441)

140(31–637)

HA enlargement

Napolitano ZhouAJR 2016; 206:W1–W10

Sensitivity 82%(71%-89%)

79% (71%–86%)

Specificity 70% (51%-84%)

75% (60%–86%)

DOR 12 (3-36)

11(5–26)

TCS Napolitano YoonUltrasoundMed2017; 36:2027–2038

ZhouAJR 2016; 206:W1–W10

Sensitivity 68% (57%-78%)

85% (77%–90%)

74% (61%–84%)

Specificity 95% (92%-97%)

97% (94%–99%)

97% (95%–99%)

DOR 40 (21-71)

175 (75–405)

101 (41–246)

Decisional flow chart Conjugated Hyperbilirubinemia (CH)

+ acholic stools

US (GBA TCS cystelastography)

Normal findingsLow suspicion

>30 days < 60 days

US liver suggestive findingsHigh suspicion

US liver suggestive findings

and syndromicpresentation

Surgery

<30 daysUS and biological test every week

Equivocal findingsvery young with partially acholic

stools, atypical patterns suggestive of medical causes

Dilation of the intrahepatic bile ducts

= rules out BA

Liver biopsy or follow-up if the

cholestasisseems to resolve

Equivocal findings

Surgery

No BALiver biopsy

PTCC or ERCP

BASurgery

Normal findings

Decisional flow chart

GBA + micro or macrocystOR

TCS + micro or macrocystOR

GBA + TCS

US liver suggestive findings and CH

<30 days

US 1-2 weeks later

Persistent GBAOR increase TCSSurgery

GBA OR TCS

>30 days

Persistent GBA and increase TCS or increase elastographyvalue

SurgeryNo BA

Liver biopsy

PTCC or ERCP

BASurgery

No BALiver biopsy

PTCC or ERCP

BASurgery

BA Take Home message

• BA is a challenging diagnosis

• Time matters

• No single test has an accuracy of 100%

• BA is a progressive disease: US signs could have a late onset

• High specificity of US signs. Careful US evaluationwith HF probes (can feed the baby once the GB is seen)

• No place for MRCP, HBS and CT!

A normal US does not rule out BA diagnosis

A special thanks to Philippe Petit and Stèphanie Franchi-Abella for sharing their BA images and expertise and Lil-Sofie Ording Müller for her precious suggestions

Abdominal ESPR Task force