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Pe d i a t r i c I m a g i n g • O r i g i n a l R e s e a r c h

Zhou et al.
Ultrasound for the Diagnosis of Biliary Atresia

Pediatric Imaging
Original Research
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FOCUS ON:

Ultrasound for the Diagnosis of


Biliary Atresia: A Meta-Analysis
Luyao Zhou1 OBJECTIVE. The purpose of this meta-analysis was to summarize the evidence on the
Quanyuan Shan accuracy of various ultrasound findings for excluding a diagnosis of biliary atresia.
Wenshuo Tian MATERIALS AND METHODS. We searched MEDLINE and the Web of Science da-
Zhu Wang tabases for the period from January 1990 to May 2015. To be included, studies had to satisfy
Jinyu Liang two criteria. First, the data needed to include 2 × 2 contingency data on the diagnostic accura-
cy of ultrasound in identifying biliary atresia in at least 10 patients with and 10 patients with-
Xiaoyan Xie
out disease. Second, the study needed to use surgery or biopsy for biliary atresia and surgery,
Zhou L, Shan Q, Tian W, Wang Z, Liang J, Xie X biopsy, clinical follow-up, or some combination of the three as the reference standard for the
exclusion of biliary atresia. The methodologic quality of each study was assessed with version
2 of the Quality Assessment of Diagnostic Accuracy Studies tool. Estimated sensitivity and
specificity of each ultrasound characteristic were calculated using a random-effects model.
RESULTS. Twenty-three studies published during 1998–2015 were included. Summary
sensitivity and specificity were 0.85 (95% CI, 0.76–0.91) and 0.92 (95% CI, 0.81–0.97), re-
spectively, for gallbladder abnormalities in 19 studies; 0.74 (95% CI, 0.61–0.84) and 0.97 (95%
CI, 0.95–0.99), respectively, for triangular cord sign in 20 studies; and 0.95 (95% CI, 0.70–
0.99) and 0.89 (95% CI, 0.79–0.94), respectively, for the combination of the triangular cord
sign and gallbladder abnormalities in five studies. Subgroup analysis of an absent gallbladder
in 10 studies yielded a summary specificity of 0.99 (95% CI, 0.93–1.00).
Keywords: biliary atresia, gallbladder, pediatrics, CONCLUSION. The triangular cord sign and gallbladder abnormalities are the two
triangular cord sign, ultrasound
most accurate and widely accepted ultrasound characteristics for diagnosing or excluding
DOI:10.2214/AJR.15.15336 biliary atresia. Other ultrasound characteristics are less valuable for diagnosis or exclusion
of biliary atresia.
Received July 23, 2015; accepted after revision
December 13, 2015.
iliary atresia remains one of the described as useful indicators for diagnosing
Supported by National Natural Science Foundation of
China (NO: 81371555) and Natural Science Foundation of
Guangdong province (NO: 2015A030313060).
B most serious liver diseases af-
fecting infants and can be fatal if
untreated [1]. The disease is un-
biliary atresia [11–17]. Before the identifica-
tion of the “triangular cord” sign by Choi et
al. [13] in 1996, gallbladder abnormalities
1 common, with frequency ranging from 1 in were the key indicators for identifying bili-
All authors: Department of Medical Ultrasonics,
Institute for Diagnostic and Interventional Ultrasound, 5000 to 1 in 20,000 live births worldwide [2– ary atresia. These abnormalities included ab-
The First Affiliated Hospital, Sun Yat-Sen University, 5]. Surgical drainage by Kasai portoenteros- sence of a gallbladder, small gallbladder size,
58 Zhongshan Rd 2, Guangzhou, 510080, China. Address tomy is more successful if performed during abnormal shape and wall of the gallbladder,
correspondence to X. Y. Xie (xxy1992sys@163.com). the early stage of the disease [6–8]. However, and no contraction of the gallbladder. Abnor-
This is an ahead-of-print version of the article; the final
in infants with conjugated hyperbilirubine- mal wall features included irregularity of the
version will appear in the May 2016 issue of the AJR. mia, identifying biliary atresia in the early wall and thinner wall without mucosa [10,
stage of the disease is challenging [9, 10]. 14, 15, 18, 19]. An abnormally shaped gall-
WEB Current modalities and techniques for bladder would typically be one with an irreg-
This is a web exclusive article.
evaluating cholestatic jaundice include ultra- ularly compromised lumen [10, 14, 18, 20].
Supplemental Data sound, hepatobiliary scintigraphy, MR chol- No contraction of the gallbladder was used to
Available online at www.ajronline.org. angiography, and liver biopsy. Among these, indicate a gallbladder that does not contract
ultrasound is recommended as the initial after feeding [21, 22]. Gallbladder abnormal-
AJR 2016; 206:W1–W10 screening examination [1, 11] because it is ities can yield both sensitivities and speci-
0361–803X/16/2065–W1
cost-effective, involves no ionizing radiation, ficities greater than 0.90 in the diagnosis of
and generally does not require sedation. Nu- biliary atresia, but accurately identifying an
© American Roentgen Ray Society merous ultrasound characteristics have been abnormal gallbladder remains a subjective

AJR:206, May 2016 W1


Zhou et al.

task, particularly for inexperienced operators the editor, review articles, case reports, and ani- ity and specificity estimates were calculated from
[10, 15, 18]. The triangular cord sign, which mal experiment studies were excluded. The refer- the extracted contingency tables. Individual study
is defined as a triangular or tubular echogen- ence lists of the included studies were manually estimates were plotted in an ROC space to high-
ic density in the vicinity of the portal vein on searched to identify other potentially eligible ar- light covariation between sensitivity and specific-
a transverse or longitudinal ultrasound im- ticles. Two reviewers, who had 5 and 3 years of ity and to explore study heterogeneity. A bivariate
age, has been described as both sensitive and experience for pediatric ultrasound independently mixed-effects regression model was used to calcu-
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specific for the diagnosis of biliary atresia evaluated all relevant studies for eligibility crite- late summary estimates of accuracy. Heterogene-
in multiple publications [10, 11, 15, 21–27]. ria. Disagreements in study selection between the ity was quantified with the I2 test statistic includ-
However, sensitivity varied in those studies two reviewers were resolved through consensus. If ing 95% CIs, with higher percentages indicating
from 0.23 to 1.00. no consensus could be reached, a third reviewer greater heterogeneity. The risk of reporting bias
Absence of a common bile duct (CBD), who had more than 5 years of experience in data was judged from funnel plots. Risk of publication
enlargement of the hepatic artery (HA), and extraction was consulted. bias was tested by a regression of the diagnostic
the identification of hepatic subcapsular flow odds ratio against the inverse of the square root of
(HSF) have also been considered useful for Data Extraction the effective sample size (ESS). Weighting by ESS
diagnosing biliary atresia [10, 11, 16, 28–30]. We extracted the following data from each indicated significant asymmetry, with p < 0.05 for
However, the correct weighting of these ul- study: study period, department of the first author, the slope coefficient [34].
trasound characteristics has not been deter- country of origin, study type (prospective or ret- We performed subgroup analyses to identify
mined, to our knowledge. rospective), and ultrasound probe frequency. Ul- factors that influence diagnostic accuracy if four
The purpose of our study was therefore to trasound characteristics included sample size, sex or more studies evaluated with the same modal-
systematically review and summarize pub- ratio, age range, cystic biliary atresia (a subtype ity were included. We also performed a subgroup
lished studies on the diagnostic performance of biliary atresia with portal cysts [20]) included analysis of studies according to the period in
of the triangular cord sign and gallbladder ab- or not, fasting time before ultrasound examina- which studies were performed.
normalities on sonography as well as the ab- tion, reference standard characteristics, and num- All statistical analyses were performed with
sence of a CBD, enlargement of the HA, and ber of true-positive, true-negative, false-positive, Stata software version 11.0 (StataCorp) and Excel
the appearance of HSF to determine whether and false-negative findings. Detailed ultrasound version 14.4 (Microsoft). A two-sided p value <
infants with jaundice also have biliary atresia. features of biliary atresia were also extracted, in- 0.05 was considered to indicate a statistically sig-
cluding the location and definition of positive tri- nificant difference.
Materials and Methods angular cord thickness, the criteria for an abnor-
This meta-analytic review was prepared with mal gallbladder, absence of a CBD, enlargement Results
reference to the Preferred Reporting Items for of the HA, and the appearance of HSF. The crite- Study and Design Characteristics
Systematic Reviews and Meta-Analysis of Obser- ria for an abnormal gallbladder were absence of Our search identified a total of 419 unique
vation Studies in Epidemiology recommendations a gallbladder; small gallbladder, such as length < references, of which 59 were deemed poten-
for study reporting [31, 32]. The protocol for this 1.5 cm; abnormal gallbladder wall or shape; and tially relevant on the basis of title or abstract.
review has not been published elsewhere. no contraction of the gallbladder after feeding. Thirty-six of the 59 relevant articles were ex-
cluded (24 articles that did not satisfy eligi-
Search Strategy Methodologic Quality Assessment bility or methods criteria, six case reports,
We searched MEDLINE and the Web of Sci- The quality of the studies was assessed using four articles in languages other than English,
ence databases for English-language articles pub- version 2 of the Quality Assessment of Diagnos- and two letters to the editor). Thus, 23 arti-
lished from January 1990 to May 2015, with key- tic Test Accuracy Studies (QUADAS-2) tool [33]. cles fulfilled all inclusion criteria and were
word indexed search terms of “(triangular cord QUADAS-2 examines seven items on the repre- selected for data extraction and analysis [10,
OR gallbladder) AND biliary atresia.” sentativeness of patient spectrum, selection crite- 11, 15, 16, 18, 19, 21, 22, 24, 25, 27, 29, 30,
ria, reference standard, verification bias, timing, 35–44] (Fig. 1).
Study Eligibility and study withdrawals. Both reviewers scored the Individual study characteristics are pre-
An article was considered potentially eligible tool independently and disagreements were re- sented in Table 1. Eleven studies were re-
if it evaluated ultrasound imaging in neonates or solved face to face by consensus. ported as prospective, 11 were reported as
infants who developed jaundice. Full-text ver- retrospective, and one did not specify type of
sions of potentially eligible articles were obtained Statistical Analysis study. Table S1 summarizes the patient char-
for further evaluation. Studies were included if all We extracted or reconstructed 2 × 2 contingen- acteristics and criteria for triangular cord
of the following inclusion criteria were met: ex- cy tables for all of the ultrasound characteristics thickness and an abnormal gallbladder in-
plicit criteria defining a positive ultrasound imag- reported in each of the included studies. If the in- cluded in the studies.
ing result; surgery, biopsy, or both used as a refer- cluded studies counted more than one type of gall- In Table 2, we present the risk of bias and
ence standard for biliary atresia; surgery, biopsy, bladder abnormality in the diagnosis of biliary the concerns regarding the applicability of
clinical follow-up, or some combination thereof atresia, only the most used and most accurate type the studies included. Twenty-one primary
used as a reference standard for the exclusion of was used for calculating the general summary studies were of high quality, obtaining low
biliary atresia; sufficient data to extract the num- ROC of abnormalities of the gallbladder. If diag- risk for six to seven items in the QUADAS
ber of true-positive, true-negative, false-positive, nostic accuracy was compared between different checklist. Two of 23 studies were of lower
and false-negative results; and sufficient data re- groups of observers, only one contingency table quality, obtaining low risk for five items in
ported for at least 10 cases. Editorials, letters to for findings by radiologists was included. Sensitiv- the QUADAS checklist. The assessment of

W2 AJR:206, May 2016


Ultrasound for the Diagnosis of Biliary Atresia

TABLE 1: Characteristics of Included Studies


First Author and First Author’s Prospective Probe
Reference No. Year Country Department Design Frequencya US Features Study Period
Ikeda [44] 1998 Japan Surgery NR 5.0 GBA 1986–1996
Lee [40] 2000 Taiwan Nuclear medicine No 5.0–7.5 GBA 1989–1999
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Tan-Kendrick [41] 2000 Singapore Diagnostic imaging Yes 5.0–10.0 TC, GBA 1997–1999
Kotb [24] 2001 Egypt Pediatrics and radiology Yes 7.0 TC, GBA NR
Farrant [18] 2001 UK Radiology Yes 13.0 GBA 1999–2000
Park [39] 2001 Korea Pediatric surgery No 7.0 TC, TC + GBA 1992–2000
Kanegawa [21] 2003 Japan Radiology Yes 5.0–8.2 TC, GBA 1996–2002
Lee [25] 2003 Korea Diagnostic radiology No 6.0–15.0 TC 1998–2001
Tan-Kendrick [15] 2003 Singapore Diagnostic imaging Yes 5.0–12.0 TC, GBA 1997–2002
Visrutaratna [38] 2003 Thailand Radiology No 7.0–10.0 TC, GBA, TC + GBA 1999–2002
Humphrey [10] 2007 UK Radiology Yes 7.5–13.5 TC, GBA, CBD absence 2002–2005
Kim [16] 2007 Korea Radiology Yes 5.0–10.0 TC, CBD absence, HA > 1.5 cm, 1999–2005
HA:PV ratio > 0.45
Takamizawa [22] 2007 Japan Surgery No 5.0–8.2 TC, GBA 1996–2006
Lee [11] 2009 Korea Radiology No 5.0–12.0 TC, GBA, HSF 2003–2007
Donia [37] 2010 Egypt Pediatrics No 3.0–5.0 TC, GBA 2008–2009
Imanieh [27] 2010 Iran Pediatric gastroenterology No 7.0 TC 2004–2008
Mittal [29] 2011 India Radiologic diagnosis and Yes 3.0–12.0 TC, GBA, CBD absence, HA > 1.5 NR
imaging cm, HA:PV ratio > 0.45, TC +
GBA
Aziz [19] 2011 USA Radiology and biomedical No 4.0–8.0 TC, GBA 2004–2009
imaging
Sun [36] 2011 China Ultrasound No 6.0–10 TC, GBA, TC + GBA 2004–2009
El-Guindi [30] 2013 Egypt Pediatric hepatology Yes 2.0–8.0 TC, GBA, HA > 2.05 mm, HSF 2009–2011
El-Guindi [35] 2014 Egypt Pediatric hepatology Yes 2.0–8.0 TC, GBA, HA > 2.05 mm, HSF, 2011–2013
HA:PV ratio > 0.445
Hanquinet [42] 2015 Switzerland Pediatric radiology No 8.0–14.0 TC, GBA NR
Zhou [43] 2015 China Medical ultrasound Yes ≥ 10 TC, GBA, HA > 1.9 cm, GB 2009–2014
classification, TC + GB
classification
Note: NR = not reported, GBA = gallbladder abnormality, TC = triangular cord sign, TC + GBA = TC and GBA combined, HA = hepatic artery diameter, RHA = right hepatic
artery, HSF = hepatic subcapsular flow, PV = portal vein diameter, CBD = common bile duct.
aReported in megahertz.

potential publication bias displayed asymme- (95% CI, 0.81–0.97) (Fig. 2A), and the area sensitivity (I2 = 93.31%, p < 0.001) and speci-
try in the funnel plot, indicating no publica- under the summary ROC curve (AUC) of ficity (I2 = 77.21%, p < 0.001).
tion bias (p = 0.29). 0.94 (95% CI, 0.91–0.95) for the detection of Meta-analysis of the five studies that
biliary atresia (Fig. 2B). The between-study used a combination of the triangular cord
Overall Diagnostic Accuracy heterogeneity was high for both sensitivity sign and an abnormal gallbladder for di-
Table 3 gives the outcomes of the meta- (I 2 = 94.89%, p < 0.001), and specificity (I 2 agnosis yielded summary sensitivity of
analysis of the different ultrasound charac- = 90.86%, p < 0.001). 0.95 (95% CI, 0.70–0.99), summary spec-
teristics used for diagnosis of biliary atresia. Meta-analysis of the 20 studies using a tri- ificity of 0.89 (95% CI, 0.79–0.94), and
Twenty studies used gallbladder abnor- angular cord sign for diagnosis yielded sum- AUC of 0.94 (95% CI, 0.92–0.96) (Fig.
malities for diagnosis [10, 11, 15, 18, 19, 21, mary sensitivity of 0.74 (95% CI, 0.61–0.84), 4A) for the diagnosis of biliary atresia [29,
22, 24, 29, 30, 35–44]. One study combined summary specificity of 0.97 (95% CI, 0.95– 36, 38, 39, 43].
abnormalities with the triangular cord sign, 0.99) (Fig. 3A), and AUC of 0.97 (95% CI, Meta-analysis of the five studies that used
so we could not extract valid data for analysis 0.95–0.98) for the diagnosis of biliary atresia HA enlargement for diagnosis yielded sum-
[39]. Meta-analysis of the remaining 19 stud- [10, 11, 15, 16, 19, 21, 22, 24, 25, 27, 29, 30, 35, mary sensitivity of 0.79 (95% CI, 0.71–0.86),
ies yielded summary sensitivity of 0.85 (95% 36, 37, 38, 39, 40, 42, 43] (Fig. 3B). The be- summary specificity of 0.75 (95% CI, 0.60–
CI, 0.76–0.91), summary specificity of 0.92 tween-study heterogeneity was high for both 0.86), and AUC of 0.83 (95% CI, 0.80–0.86)

AJR:206, May 2016 W3


TABLE 2: Patient Selection
Zhou et al.
Risk of Bias Applicability Concerns
Year of Patient Reference Patient Reference
Publication First Author Selection Index Test Standard Flow and Timing Selection Index Test Standard
1998 Ikeda Low Low Low Unclear Low Low Low
2000 Lee Low Low Low Low Low Low Low
2000 Tan-Kendrick Low Low Low High Low Low Low
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2001 Kotb Low Low Low Low Low Low Low


2001 Farrant Low Low Low Low Low Low Low
2001 Park Low Low Low Low Low Low Low
2003 Kanegawa Low Low Low High Low Low Low
2003 Lee Low Low Low High Unclear Low Low
2003 Tan-Kendrick Low Low Low High High Low Low
2003 Visrutaratna Low Low Low High Low Low Low
2007 Humphrey Low Low Low Low Low Low Low
2007 Kim Low Low Low Low Low Low Low
2007 Takamizawa Low Low Low Unclear Low Low Low
2009 Lee Low Low Low Low Low Low Low
2010 Donia Low Low Low High Low Low Low
2010 Imanieh Low Low Low High Low Low Low
2011 Mittal Low Low Low Unclear Low Low Low
2011 Aziz Low Low Low Low Low Low Low
2011 Sun Low Low Low Unclear Low Low Low
2013 El-Guindi Low Low Low High Low Low Low
2014 El-Guindi Low Low Low High Low Low Low
2015 Hanquinet Low Low Low Low Low Low Low
2015 Zhou Low Low Low Low Low Low Low

(Fig. 4B) for the diagnosis of biliary atresia normalities and HA enlargement. Although sign and a gallbladder abnormality might in-
[16, 29, 30, 35, 43]. the summary sensitivity of the triangu- crease the combined sensitivity to a higher
lar cord sign is as low as 0.74, the summa- level. Because biliary atresia is a severe dis-
Subgroup Analysis ry specificity of 0.97 is the highest among ease, higher sensitivity will benefit infants
Table 4 sets out the results of the subgroup all ultrasound characteristics. The accuracy who are suspected to have biliary atresia.
analysis of gallbladder abnormalities and the for gallbladder abnormalities (AUC = 0.94) Our review found that an abnormal gall-
triangular cord sign for the diagnosis of bili- is similar to the accuracy for the combina- bladder is the most widely accepted crite-
ary atresia. tion of the triangular cord sign and gallblad- rion for differentiating biliary atresia from
der abnormalities. However, the summary other causes of infantile jaundice. Of 23 eli-
Discussion sensitivity (0.95) of the combination of the gible studies, both gallbladder abnormalities
In our systematic review, we observed that triangular cord sign and gallbladder abnor- and the triangular cord sign were mentioned
the triangular cord sign had the highest diag- malities is superior to that of gallbladder ab- as an ultrasound characteristic in 20 stud-
nostic accuracy for detection of biliary atre- normalities or the triangular cord sign alone. ies, followed by HA enlargement, which was
sia (AUC = 0.97), followed by gallbladder ab- Thus, the combination of the triangular cord mentioned in five studies [16, 29, 35]. The ab-
sence of CBD [10, 29, 30] and HSF was re-
TABLE 3: Outcomes of Meta-Analysis of Different Ultrasound Features in ported in three studies. The least frequent-
Diagnosis of Biliary Atresia
ly mentioned ultrasound characteristics was
Ultrasound No. of HA/portal vein (PV) ratio, which was only
Feature Studies Sensitivity Specificity DOR AUC reported in only two studies [16, 35]. These
GBA 19 0.85 (0.76–0.91) 0.92 (0.81–0.97) 61 (18–204) 0.94 (0.91–0.95) data indicate that abnormalities of the gall-
bladder and the triangular cord sign are the
TC 20 0.74 (0.61–0.84) 0.97 (0.95–0.99) 101 (41–246) 0.97 (0.95–0.98)
most reliable and the most widely used ultra-
TC + GBA 5 0.95 (0.70–0.99) 0.89 (0.79–0.94) 140 (31–637) 0.94 (0.92–0.96) sound characteristics used for the diagnosis
HA enlargement 5 0.79 (0.71–0.86) 0.75 (0.60–0.86) 11 (5–26) 0.83 (0.80–0.86) of biliary atresia. The difficulty in identify-
Note—Values in parentheses are 95% CIs. DOR = diagnostic odds ratio, GBA = gallbladder abnormality, TC = ing the CBD in healthy infants even with a
triangular cord sign, TC + GBA = TC and GBA combined, HA = hepatic artery. high-resolution probe may explain why the

W4 AJR:206, May 2016


Ultrasound for the Diagnosis of Biliary Atresia

TABLE 4: Subgroup Analysis of Gallbladder Abnormality and Triangular Cord Sign


Subgroup No. of Studies Sensitivity Specificity DOR AUC
GBA
Absence 10 0.28 (0.19–0.40) 0.99 (0.93–1.00) 47 (7–340) 0.64 (0.60–0.68)
Absence or length < 1.5 cm 6 0.79 (0.66–0.88) 0.87 (0.65–0.96) 26 (6–106) 0.86 (0.83–0.89)
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Wall abnormality 5 0.83 (0.70–0.91) 0.94 (0.91–0.96) 82 (30–223) 0.96 (0.94–0.97)


No contractiona 5 0.89 (0.81–0.93) 0.79 (0.55–0.92) 30 (11–79) 0.90 (0.87–0.92)
TC
Location
Bifurcation 10 0.80 (0.58–0.92) 0.99 (0.96–1.00) 427 (62–2928) 0.98 (0.97–0.99)
EARPV 6 0.63 (0.55–0.71) 0.95 (0.89–0.98) 33 (12–87) 0.74 (0.70–0.77)
Thickness
≥4 mm 7 0.60 (0.46–0.72) 0.97 (0.94–0.99) 54 (17–171) 0.94 (0.92–0.96)
Cutoff value not mentioned 9 0.74 (0.48–0.90) 0.99 (0.94–1.00) 288 (23–3583) 0.98 (0.96–0.99)
Study periodb
2000 or before 8 0.87 (0.77–0.93) 0.98 (0.93–1.00) 371 (80–1728) 0.97 (0.95–0.98)
After 2000 10 0.58 (0.41–0.73) 0.96 (0.93–0.98) 33 (15–76) 0.96 (0.93–0.97)
Note—Values in parentheses are 95% CIs. DOR = diagnostic odds ratio, EARPV = echogenic anterior wall of the right portal vein.
aNo contraction was defined as a gallbladder that did not contract after feeding.
bStudy period of 2000 or before contains studies with objects initiated in 2000 or before. Study period after 2000 contains studies with all the objects initiated after 2000.

absence of the CBD is not more widely used mary sensitivity of 0.63 (95% CI, 0.55–0.71) mits evaluation of the existence of an extrahe-
for diagnosis. Furthermore, because HSF is and an AUC of 0.74 (95% CI, 0.70–0.77), patic bile duct [47, 48]. The accuracy of MR
highly dependent on both the operator’s ex- which were lower than the corresponding cholangiography could be improved with IV
perience and the scanner condition, differ- values for triangular cords located at the por- administration of a contrast agent. However,
ent operators from different institutions will tal vein bifurcation. Moreover, the diagnostic infants undergoing the procedure require oral
have difficulty achieving consistent results. performance of a triangular cord thickness or deep IV sedation [47, 48].
Although diagnostic performance of gall- of 4 mm or more in seven studies was not as Liver biopsy is recommended for in-
bladder abnormalities was below that of trian- good as that in studies that did not mention fants in whom noninvasive procedures yield
gular cord thickness, subgroup analysis found a cutoff value, which indicates that this char- equivocal results [49]. The diagnostic ac-
that an absent gallbladder could yield a sum- acteristic is not a useful diagnostic tool. The curacy of liver biopsy for biliary atresia is
mary specificity of 0.99, which is comparable assumption that the triangular cord thick- 90% or greater [24, 50]. However, when per-
to that of the triangular cord sign. Further- ness in infants with early-stage biliary atre- formed early in the course of biliary atre-
more, the diagnostic accuracy of gallblad- sia was less than 4 mm might be one explana- sia, biopsy can incorrectly appear to indicate
ders with abnormal walls is best among all tion for this outcome [45]. Subgroup analysis hepatitis [13, 51]. Studies have shown the di-
types of gallbladder abnormalities. The sub- also showed that although the summary sen- agnostic accuracy of ultrasound to be supe-
group analysis results also indicated the crite- sitivities of different types of the triangular rior to that of liver biopsy in the diagnosis of
ria for determining gallbladder abnormalities cord sign varied substantially, the specifici- biliary atresia [23, 24].
varied between studies, which might help ex- ties were always high. Most studies included in this meta-analy-
plain discrepancies in the diagnostic accura- Hepatobiliary scintigraphy was an im- sis used the triangular cord sign as a diagnos-
cy of different studies. Correct identification portant diagnostic modality for distinguish- tic characteristic, and surgery and biopsy were
of different types of abnormal gallbladders ing biliary atresia from neonatal hepatitis. used as reference standards, with a wide range
could improve the diagnostic accuracy of ul- This procedure had summary sensitivity of of sensitivities (0.23–1.00) and specificities
trasound for the detection of biliary atresia. 0.987, but its summary specificity was as low (0.48–1.00). These differences may be the re-
However, identifying an abnormal gallblad- as 0.704 [46]. Our meta-analysis showed the sult of a number of factors. First, the technical
der on ultrasound remains a subjective task specificity of ultrasound is much better than quality and performance of ultrasound varied
[10]. A more objective gallbladder classifica- that of scintigraphy for the diagnosis of bil- across studies. We included studies conduct-
tion system that could unify all these crite- iary atresia. Several of the included studies ed from 1998 to 2014; technologic advances
ria may improve the diagnostic accuracy [43]. also found that the specificity and accuracy of in ultrasound equipment may explain some of
Subgroup analysis of the triangular cord ultrasound were better than that for scintig- the variation. However, subgroup analysis ac-
sign showed that triangular cords located at raphy [10, 24, 47]. MR cholangiography was cording to study period showed no difference
the echogenic anterior wall of the right portal another useful imaging modality for diagnos- between studies performed up to 2000 and
vein (EARPV) in six studies yielded a sum- ing or excluding biliary atresia because it per- those performed after 2000. Second, the cri-

AJR:206, May 2016 W5


Zhou et al.

teria used to define a positive triangular cord 5. Hsiao CH, Chang MH, Chen HL, et al. Universal 21. Kanegawa K, Akasaka Y, Kitamura E, et al. Sono-
sign differed across studies. Third, the com- screening for biliary atresia using an infant stool col- graphic diagnosis of biliary atresia in pediatric
position of patients (i.e., some included cys- or card in Taiwan. Hepatology 2008; 47:1233–1240 patients using the “triangular cord” sign versus
tic biliary atresia and some excluded cystic 6. Sokol RJ, Shepherd RW, Superina R, Bezerra JA, gallbladder length and contraction. AJR 2003;
biliary atresia) among studies was different. Robuck P, Hoofnagle JH. Screening and outcomes 181:1387–1390
The prevalence of the triangular cord sign be- in biliary atresia: summary of a National Institutes 22. Takamizawa S, Zaima A, Muraji T, et al. Can bili-
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tween cystic biliary atresia and general biliary of Health workshop. Hepatology 2007; 46:566–581 ary atresia be diagnosed by ultrasonography
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the accuracy of gallbladder abnormalities be- Gastroenterol Nutr 2008; 46:299–307 Lee SL. A new diagnostic approach to biliary
tween studies. 8. Serinet MO, Wildhaber BE, Broue P, et al. Impact atresia with emphasis on the ultrasonographic tri-
Finally, considerable heterogeneity in of age at Kasai operation on its results in late child- angular cord sign: comparison of ultrasonogra-
the sensitivity and specificity values across hood and adolescence: a rational basis for biliary phy, hepatobiliary scintigraphy, and liver needle
studies was observed in our systematic re- atresia screening. Pediatrics 2009; 123:1280–1286 biopsy in the evaluation of infantile cholestasis.
view. The heterogeneity was mainly caused 9. Kim GC, Choe BH, Lee SY, Ryeom HK. Triangu- J Pediatr Surg 1997; 32:1555–1559
by variations in study design, patient char- lar cord sign in biliary atresia: does it have prog- 24. Kotb MA, Kotb A, Sheba MF, et al. Evaluation of
acteristics, technical aspects of the imaging nostic and medicolegal significance? (response to the triangular cord sign in the diagnosis of biliary
modalities, and data reporting. We used a letter) Radiology 2012; 263:621–622 atresia. Pediatrics 2001; 108:416–420
random-effects meta-analysis to address the 10. Humphrey TM, Stringer MD. Biliary atresia: US 25. Lee HJ, Lee SM, Park WH, Choi SO. Objective
heterogeneous data. Because the 95% CIs diagnosis. Radiology 2007; 244:845–851 criteria of triangular cord sign in biliary atresia on
were not wide, we believe that our results are 11. Lee MS, Kim MJ, Lee MJ, et al. Biliary atresia: US scans. Radiology 2003; 229:395–400
valid. Nevertheless, heterogeneity in diag- color Doppler US findings in neonates and infants. 26. Li SX, Zhang Y, Sun M, et al. Ultrasonic diagnosis
nostic studies remains a concern and may in- Radiology 2009; 252:282–289 of biliary atresia: a retrospective analysis of 20 pa-
fluence the certainty of the conclusions. 12. Ikeda S, Sera Y, Akagi M. Serial ultrasonic ex- tients. World J Gastroenterol 2008; 14:3579–3582
amination to differentiate biliary atresia from 27. Imanieh MH, Dehghani SM, Bagheri MH, et al.
Conclusion neonatal hepatitis: special reference to changes in Triangular cord sign in detection of biliary atresia:
The triangular cord sign and gallbladder size of the gallbladder. Eur J Pediatr 1989; is it a valuable sign? Dig Dis Sci 2010; 55:172–175
abnormalities are the two most accurate and 148:396–400 28. Azuma T, Nakamura T, Nakahira M, Harumoto
widely accepted ultrasound characteristics 13. Choi SO, Park WH, Lee HJ, Woo SK. ‘Triangular K, Nakaoka T, Moriuchi T. Pre-operative ultraso-
currently used for the diagnosis or exclusion cord’: a sonographic finding applicable in the diag- nographic diagnosis of biliary atresia with refer-
of biliary atresia. The combination of the nosis of biliary atresia. J Pediatr Surg 1996; ence to the presence or absence of the extrahepatic
triangular cord sign and gallbladder abnor- 31:363–366 bile duct. Pediatr Surg Int 2003; 19:475–477
malities can improve diagnostic sensitivity. 14. Farrant P, Meire HB, Mieli-Vergani G. Ultrasound 29. Mittal V, Saxena AK, Sodhi KS, et al. Role of ab-
The absence of a gallbladder is as specific as features of the gall bladder in infants presenting dominal sonography in the preoperative diagnosis
the triangular cord sign in the diagnosis of with conjugated hyperbilirubinaemia. Br J Radiol of extrahepatic biliary atresia in infants younger
biliary atresia. Other ultrasound character- 2000; 73:1154–1158 than 90 days. AJR 2011; 196:[web]W438–W445
istics, including the absence of a CBD, en- 15. Tan-Kendrick AP, Phua KB, Ooi BC, Tan CE. Bili- 30. El-Guindi MA, Sira MM, Konsowa HA, El-Abd OL,
largement of the HA, and the appearance of ary atresia: making the diagnosis by the gallbladder Salem TA. Value of hepatic subcapsular flow by color
HSF, are less valuable findings for diagnosis. ghost triad. Pediatr Radiol 2003; 33:311–315 Doppler ultrasonography in the diagnosis of biliary
A detailed ultrasound examination for the 16. Kim WS, Cheon JE, Youn BJ, et al. Hepatic arte- atresia. J Gastroenterol Hepatol 2013; 28:867–872
triangular cord sign and for gallbladder ab- rial diameter measured with US: adjunct for US 31. Stroup DF, Berlin JA, Morton SC. Meta-analysis
normalities could reduce the need for liver diagnosis of biliary atresia. Radiology 2007; of observational studies in epidemiology: a pro-
biopsies and hepatobiliary scintigraphy for 245:549–555 posal for reporting. JAMA 2000;283:2008–2012
infants suspected to have biliary atresia. 17. Lee SY, Kim GC, Choe BH, et al. Efficacy of US- 32. Moher D, Liberati A, Tetzlaff J, Altman DG;
guided percutaneous cholecystocholangiography PRISMA Group. Preferred reporting items for sys-
References for the early exclusion and type determination of tematic reviews and meta-analyses: the ­PRISMA
1. Hartley JL, Davenport M, Kelly DA. Biliary atre- biliary atresia. Radiology 2011; 261:916–922 statement. PLoS Med 2009;6:e1000097
sia. Lancet 2009; 374:1704–1713 18. Farrant P, Meire HB, Mieli-Vergani G. Improved 33. Whiting PF, Rutjes AW, Westwood ME, et al.
2. Yoon PW, Bresee JS, Olney RS, James LM, Khoury diagnosis of extraheptic biliary atresia by high QUADAS-2: a revised tool for the quality assess-
MJ. Epidemiology of biliary atresia: a population- frequency ultrasound of the gall bladder. Br J ment of diagnostic accuracy studies. Ann Intern
based study. Pediatrics 1997; 99:376–382 ­Radiol 2001; 74:952–954 Med 2011; 155:529–536
3. Chardot C, Carton M, Spire-Bendelac N, Le Pom- 19. Aziz S, Wild Y, Rosenthal P, Goldstein RB. Pseu- 34. Deeks JJ, Macaskill P, Irwig L. The performance of
melet C, Golmard JL, Auvert B. Epidemiology of do gallbladder sign in biliary atresia: an imaging tests of publication bias and other sample size effects
biliary atresia in France: a national study 1986-96. pitfall. Pediatr Radiol 2011; 41:620–626 in systematic reviews of diagnostic test accuracy was
J Hepatol 1999; 31:1006–1013 20. Zhou LY, Guan BY, Li L, et al. Objective differential assessed. J Clin Epidemiol 2005; 58:882–893
4. McKiernan PJ, Baker AJ, Kelly DA. The frequen- characteristics of cystic biliary atresia and choledoch- 35. El-Guindi MA, Sira MM, Sira AM, et al. Design
cy and outcome of biliary atresia in the UK and al cysts in neonates and young infants: sonographic and validation of a diagnostic score for biliary
Ireland. Lancet 2000; 355:25–29 findings. J Ultrasound Med 2012; 31:833–841 atresia. J Hepatol 2014; 61:116–123 [Erratum in

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J Hepatol 2015; 63:289] ASW, Ooi BC, Tan CE. Making the diagnosis of ture. Pediatr Radiol 2013; 43:905–919
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and infantile hepatitis syndrome. Pediatr Surg Int 42. Hanquinet S, Courvoisier DS, Rougemont AL, et al. hanced MR cholangiography for evaluation.
2011; 27:675–679 Contribution of acoustic radiation force impulse ­Radiology 2005; 235:250–258
37. Donia AE, Ibrahim SM, Kader MS, et al. Predic- (ARFI) elastography to the ultrasound diagnosis of 48. Kim MJ, Park YN, Han SJ, et al. Biliary atresia in
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tive value of assessment of different modalities in biliary atresia. Pediatr Radiol 2015; 45:1489–1495 neonates and infants: triangular area of high sig-
the diagnosis of infantile cholestasis. J Int Med 43. Zhou LY, Wang W, Shan QY, et al. Optimizing the nal intensity in the porta hepatis at T2-weighted
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Records identified
through database
searching (n = 419)

Records after
duplicates
removed (n = 257)

Records Records excluded


screened by title or abstract
(n = 257) (n = 198)

Full-text articles Full-text


assessed for articles excluded
eligibility (n = 59) (n = 36; 24 did not
satisfy eligibility
or methods
Full-text articles criteria, 6 case
assessed for reports, 4 not in
eligibility (n = 23) English, 2 letters)
Fig. 1—Flow diagram of study selection.

AJR:206, May 2016 W7


Zhou et al.

Study Sensitivity (95% CI) Study Specificity (95% CI)

Hanquinet 2015 0.40 (0.12–0.74) Hanquinet 2015 1.00 (0.69–1.00)


Zhou 2015 0.87 (0.80–0.92) Zhou 2015 0.90 (0.84–0.95)
El-Guindi 2014 0.77 (0.58–0.90) El-Guindi 2014 0.77 (0.59–0.90)
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El-Guindi 2013 0.93 (0.76–0.99) El-Guindi 2013 0.48 (0.29–0.68)


Sun 2011 0.36 (0.28–0.44) Sun 2011 0.83 (0.64–0.94)
Mittal 2011 0.83 (0.65–0.94) Mittal 2011 0.83 (0.72–0.91)
Aziz 2011 1.00 (0.78–1.00) Aziz 2011 1.00 (0.83–1.00)
Donia 2010 0.64 (0.44–0.81) Donia 2010 0.82 (0.60–0.95)
Lee 2009 0.66 (0.46–0.82) Lee 2009 0.74 (0.57–0.88)
Takamizawa 2007 0.87 (0.66–0.97) Takamizawa 2007 0.72 (0.55–0.86)
Humphrey 2007 0.70 (0.47–0.87) Humphrey 2007 1.00 (0.94–1.00)
Visrutaratna 2003 0.96 (0.78–1.00) Visrutaratna 2003 0.70 (0.47–0.87)
Tan-Kendrick 2003 0.97 (0.83–1.00) Tan-Kendrick 2003 1.00 (0.98–1.00)
Kanegawa 2003 0.85 (0.55–0.98) Kanegawa 2003 0.73 (0.52–0.88)
Kotb 2001 0.92 (0.74–0.99) Kotb 2001 0.75 (0.59–0.87)
Farrant 2001 0.92 (0.78–0.98) Farrant 2001 0.97 (0.92–0.99)
Lee 2000 0.82 (0.68–0.91) Lee 2000 0.63 (0.53–0.72)
Tan-Kendrick 2000 1.00 (0.74–1.00) Tan-Kendrick 2000 1.00 (0.93–1.00)
Ikeda 1998 0.88 (0.70–0.98) Ikeda 1998 1.00 (0.91–1.00)

All studies 0.85 (0.76–0.91) All studies 0.92 (0.81–0.97)


Q = 352.35, df = 18.00, p = 0.00 Q = 197.04, df = 18.00, p = 0.00
I 2 = 94.89 (93.45–96.33) I 2 = 90.86 (87.79–93.94)

0.1 1.0 0.3 1.0


Sensitivity Specificity

A
Fig. 2—Gallbladder abnormalities for diagnosis.
A, Forest plots of sensitivity and specificity of gallbladder abnormalities for diagnosis. 1.0
B, Summary ROC curve (solid line, AUC = 0.94 [95% CI, 0.91–0.95]) with 95%
prediction contour (dotted line) and confidence contour (dashed line). Black
diamond = summary operating point (sensitivity, 0.85 [95% CI, 0.76–0.91];
specificity, 0.92 [95% CI, 0.81–0.97]); circles = observed data points.
Sensitivity

0.5

0
1.0 0.5 0
Specificity

W8 AJR:206, May 2016


Ultrasound for the Diagnosis of Biliary Atresia

Study Sensitivity (95% CI) Study Specificity (95% CI)

Zhou 2015 0.92 (0.86–0.96) Zhou 2015 0.94 (0.89–0.98)


Hanquinet 2015 0.70 (0.35–0.93) Hanquinet 2015 0.90 (0.55–1.00)
El-Guindi 2014 0.63 (0.44–0.80) El-Guindi 2014 0.87 (0.69–0.96)
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El-Guindi 2013 0.59 (0.39–0.78) El-Guindi 2013 0.89 (0.71–0.98)


Sun 2011 0.27 (0.20–0.35) Sun 2011 0.97 (0.83–1.00)
Aziz 2011 0.60 (0.32–0.84) Aziz 2011 0.95 (0.75–1.00)
Mittal 2011 0.23 (0.10–0.42) Mittal 2011 0.97 (0.90–1.00)
Imanieh 2010 0.70 (0.35–0.93) Imanieh 2010 0.96 (0.86–0.99)
Donia 2010 0.19 (0.06–0.38) Donia 2010 1.00 (0.85–1.00)
Lee 2009 0.62 (0.42–0.79) Lee 2009 1.00 (0.90–1.00)
Takamizawa 2007 0.85 (0.72–0.94) Takamizawa 2007 0.95 (0.82–0.99)
Kim 2007 0.58 (0.41–0.74) Kim 2007 0.93 (0.78–0.99)
Humphrey 2007 0.73 (0.54–0.88) Humphrey 2007 1.00 (0.94–1.00)
Visrutaratna 2003 0.96 (0.78–1.00) Visrutaratna 2003 0.74 (0.52–0.90)
Tan-Kendrick 2003 0.84 (0.66–0.95) Tan-Kendrick 2003 1.00 (0.98–1.00)
Lee 2003 0.80 (0.56–0.94) Lee 2003 0.98 (0.92–1.00)
Kanegawa 2003 0.93 (0.77–0.99) Kanegawa 2003 0.96 (0.80–1.00)
Park 2001 0.83 (0.65–0.94) Park 2001 0.98 (0.91–1.00)
Kotb 2001 1.00 (0.86–1.00) Kotb 2001 1.00 (0.91–1.00)
Tan-Kendrick 2000 0.83 (0.52–0.98) Tan-Kendrick 2000 1.00 (0.93–1.00)

All studies 0.74 (0.61–0.84) All studies 0.97 (0.95–0.99)


Q = 297.87, df = 19.00, p = 0.00 Q = 7937.04, df = 19.00, p = 0.00
I 2 = 93.62 (91.74–95.50) I 2 = 76.06 (87.79–66.36)

0.1 1.0 0.3 1.0


Sensitivity Specificity

A
Fig. 3—Triangular cord sign for diagnosis.
A, Forest plots of sensitivity and specificity. 1.0
B, Summary ROC curve (solid line, AUC = 0.97 [95% CI, 0.95–0.98]) with 95%
prediction contour (dotted line) and confidence contour (dashed line). Black
diamond = summary operating point (sensitivity, 0.74 [95% CI, 0.61–0.84];
specificity, 0.97 [95% CI, 0.95–0.99]); circles = observed data points.
Sensitivity

0.5

0
1.0 0.5 0
Specificity

AJR:206, May 2016 W9


Zhou et al.

1.0 1.0
Downloaded from www.ajronline.org by Gazi Universitesi on 03/27/16 from IP address 194.27.18.18. Copyright ARRS. For personal use only; all rights reserved

Sensitivity

Sensitivity
0.5 0.5

0 0
1.0 0.5 0 1.0 0.5 0
Specificity Specificity

A B
Fig. 4—Summary ROC curves (solid lines) with 95% prediction contour (dotted lines) and confidence contour (dashed lines). Circles = observed data points.
A, Triangular cord sign and abnormal gallbladder for diagnosis. AUC is 0.94 (95% CI, 0.92–0.96). Black diamond = summary operating point (sensitivity, 0.95 [95% CI,
0.70–0.99]; specificity, 0.89 [95% CI, 0.79–0.94]).
B, Hepatic artery enlargement for diagnosis. AUC is 0.83 (95% CI, 0.80–0.86). Black diamond = summary operating point (sensitivity, 0.79 [95% CI, 0.71–0.86]; specificity,
0.75 [95% CI, 0.60–0.86]).

F O R YO U R I N F O R M AT I O N
A data supplement for this article can be viewed in the online version of the article at: www.ajronline.org.

W10 AJR:206, May 2016

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