1300 Original article
Common misdiagnoses of biliary atresia Mostafa M. Siraa, Mohammad Tahab and Ahmad M. Siraa Objectives Discrimination of biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. We aimed to analyze the clinicopathological findings in cholestatic infants who were provisionally diagnosed with BA and then excluded by intraoperative cholangiography compared with those with a definitive diagnosis of BA and to shed light on common misdiagnoses of BA. Methods We retrospectively analyzed the data of infants diagnosed preoperatively with BA and referred to surgery between the years 2009 and 2013. On the basis of intraoperative cholangiography results, infants were divided into those with a definitive diagnosis of BA and those misdiagnosed with BA. Results Out of 147 infants, there was a misdiagnosis of BA in 10 (6.8%) infants. Alanine transaminase was significantly higher in the non-BA group, whereas other clinical and laboratory findings were comparable in both groups. Hepatomegaly and abnormal gallbladder in ultrasound, and ductular proliferation and advanced grades of portal fibrosis in liver biopsy were significantly higher in infants with BA. However, giant cells were more common in the non-BA infants. Nonetheless, the frequency of clay stool, hepatomegaly, abnormal gallbladder, ductular proliferation, and advanced portal fibrosis was remarkable (100, 70, 40,
Introduction Biliary atresia (BA) is the most common cause of chronic cholestasis in neonates and infants. It constitutes nearly one-third of all neonatal cholestasis (NC) and more than 90% of obstructive cholestatic cases [1]. BA is a destructive inflammatory obliterative cholangiopathy that affects varying lengths of both intrahepatic and extrahepatic bile ducts [2]. If untreated, BA leads to cirrhosis, hepatic failure, and death within the first 2 years of life [3]. The diagnosis of BA, particularly distinguishing it from other causes of liver injury in the neonatal period, is challenging as there is a high degree of overlap in the clinical, biochemical, imaging, and histopathological characteristics of BA and other causes of NC [4]. There is no single preoperative investigation that enables the diagnosis of BA to be made with certainty [5]. The histopathological features can overlap with other pediatric cholestatic liver diseases. In some cases, specimen interpretation is complicated by equivocal histopathological findings or atypical clinical and radiological findings [4]. The most useful distinguishing histopathological feature in BA is the portal fibrosis and bile duct proliferation; nonetheless, a similar pattern may be found in 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
70, and 50%, respectively) in the misdiagnosed infants. The misdiagnoses were idiopathic neonatal hepatitis, progressive familial intrahepatic cholestasis type 3, cytomegalovirus hepatitis, Alagille syndrome, and a cholangitic form of congenital hepatic fibrosis. Conclusion A meticulous preoperative workup should be performed to exclude other causes of NC even if signs of BA are present, especially if features such as giant cells in histopathology are present. This involves completing the NC workup in parallel involving all common causes of NC rather than performing them in series to avoid loss of valuable time and efforts. Eur J Gastroenterol Hepatol 26:1300–1305 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:1300–1305 Keywords: biliary atresia, intraoperative cholangiography, liver biopsy, misdiagnoses, neonatal cholestasis Departments of aPediatric Hepatology and bHepatobiliary Surgery, National Liver Institute, Menofiya University, 32511, Shebin El-koom, Menofiya, Egypt Correspondence to Mostafa M. Sira, MD, Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt Tel: + 20 48 222 2740; fax: + 20 48 223 4586; e-mail: [email protected] Received 14 March 2014 Accepted 28 July 2014
other causes of nonobstructive cholestasis such as alpha 1 antitrypsin deficiency disease, cystic fibrosis, and progressive familial intrahepatic cholestasis (PFIC) type 3 [6]. A constellation of clinical, laboratory, and ultrasonographic findings raises the suspicion of BA, which is supported by features of biliary outflow obstruction in liver biopsy and confirmed by laparotomy or intraoperative cholangiography (IOC) before surgery. Some infants may exhibit patent biliary tree, BA is then excluded [7]. The aim of this retrospective study was to analyze the clinicopathological findings in cholestatic infants who were provisionally diagnosed with BA and then excluded by IOC compared with those in infants with a definitive diagnosis of BA and to shed light on certain etiologies that can, still, be misdiagnosed as BA despite an extensive preoperative diagnostic workup in specialized tertiary centers.
Patients and methods Study population
This retrospective study included 147 infants with cholestasis attending the Pediatric Hepatology Department DOI: 10.1097/MEG.0000000000000198
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Misdiagnoses of BA Sira et al. 1301
in the period between year 2009 and 2013, who were provisionally diagnosed with BA. They were referred to the Department of Hepatobiliary Surgery, National Liver Institute, for Kasai portoenterostomy. According to the results of laparotomy and IOC, infants were divided into two groups. The first group (BA group) included infants with a definitive diagnosis of BA. The second group (non-BA cholestasis group) included cholestatic infants in whom BA was ruled out by confirming the patent biliary system by IOC.
Statistical analysis
Descriptive results were expressed as mean ± SD or number (percentage) of individuals with a condition. For quantitative data, statistical significance between individual groups was tested using the Mann–Whitney U nonparametric test. For qualitative data, significance between groups was tested using the χ2-test. Results were considered significant if P-value was up to 0.05. Statistical analysis was carried out using SPSS, version 13 (SPSS Inc., Chicago, Illinois, USA).
Data collection
Preoperative demographic (age and sex), clinical and laboratory data including total and direct bilirubin, transaminases [alanine transaminase (ALT) and aspartate transaminase], biliary enzymes [gammaglutamyl transpeptidase (GGT) and alkaline phosphatase], total proteins, serum albumin, and international normalized ratio were determined. Ultrasonographic findings in the form of liver and spleen size, ascites, contractility of gallbladder, and triangular cord sign were all listed. Contractile gallbladder was defined by the change in gallbladder dimensions on ultrasonography 30 min postprandial compared with its basal size after 4 h of fasting. The gallbladder was considered abnormal if no change of its dimensions was observed, if its length was less than 20.5 mm [5], or if it was not visualized [8]. Hepatic histopathological features in the form of portal fibrosis, ductular proliferation, bile plugs, intracellular cholestasis, portal cellular infiltrate, and multinucleated giant hepatocyte were also revised. The study was approved by the Research Ethics Committee of the National Liver Institute, Menofiya University, Egypt.
Results Population characteristics
Out of the 147 infants, there was a misdiagnosis of BA in 10 cases, with an overall misdiagnosis rate of 6.8% in a 5-year period. BA was excluded on the basis of IOC showing a patent biliary system (Fig. 1). The mean age of infants in the BA group was 65.49 ± 25.17 days and that of the infants in the non-BA group was 71.1 ± 12.49 days, with no significant statistical difference (P = 0.208). There were 62 male infants (45.3%) in the BA versus seven male infants (70%) in the non-BA group (P = 0.13). Idiopathic neonatal hepatitis (INH) and PFIC type 3 were found in the majority (60%) of the infants in the non-BA group (Fig. 2).
Fig. 1
Intraoperative cholangiography
Traditionally, the operation is performed under general anesthesia, where the patient lies in the supine position and a small right upper abdominal quadrant transverse or oblique incision is made. The abdomen is explored; if no gallbladder or a fibrotic gallbladder and/or atretic extrahepatic biliary tree are present, no cholangiogram is performed and Kasai portoenterostomy is performed. If a gallbladder is visualized and is patent, an operative cholangiogram is the next maneuver, wherein the tip of the gallbladder is cannulated with a 24 G intravenous cannula and a burse string is taken around its entrance to prevent the leak of the contrast (Urografin 76%; BerliMed S.A., Madrid, Spain or Ultravist; Bayer HealthCare Pharmaceuticals Inc., Berlin, Germany), which is instilled under fluoroscopy (Philips BV 25 gold C-Arm; Philips Medical Systems, Eindhoven, The Netherlands). If the contrast flows into the duodenum and into the intrahepatic bile ducts, BA is ruled out. At that time, a wedge liver biopsy is performed, the catheter is removed, and the incision is closed.
Nati Ins
PHILIPS BV25 gold
6 3 2 4 1
5 c
Intraoperative cholangiography. A case of non-BA where the contrast introduced through the cannula (1) flows from the gallbladder (2) to the cystic duct (3), then into the duodenum (4) through the common bile duct, which was then clamped by bulldog forceps, (5) to reveal the patency of common hepatic and right and left hepatic ducts (6). BA, biliary atresia.
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1302 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
significantly higher in BA than that in non-BA infants, whereas there was no statistically significant difference between both groups in other parameters such as splenomegaly, ascites, and triangular cord sign. The occurrence of polyspenia was only found in BA infants (Table 2).
Fig. 2
CHF 1 (10%)
AGS 1 (10%)
INH 3 (30%)
CMV 2 (20%)
Histopathological features
PFIC3 3 (30%)
Misdiagnoses of biliary atresia. AGS, Alagille syndrome (n = 1); CHF, congenital hepatic fibrosis – cholangitic type (n = 1); CMV, cytomegalovirus hepatitis (n = 2); INH, idiopathic neonatal hepatitis (n = 3); PFIC3, progressive familial intrahepatic cholestasis type 3 (n = 3).
Ductular proliferation and advanced grades of portal fibrosis were significantly higher in the BA group than that in the non-BA group (P = 0.003 for both), whereas multinucleated giant hepatocytes were significantly higher in the non-BA than in the BA group (P = 0.009). There was no statistically significant difference between both groups in bile plugs, intracellular bile pigments, or portal cellular infiltrate (Table 3).
Discussion Clinical and laboratory findings
The clinical presentation of all the infants that first attracts attention was jaundice and clay stool in the majority of cases. There was no statistically significant difference in the clinical findings and laboratory parameters between the BA and the non-BA infants, except for ALT, which was significantly higher in non-BA infants (220.5 ± 125.48 vs. 152.4 ± 123.88; P = 0.018) (Table 1). Ultrasonographic parameters
On comparing the ultrasonographic findings between both groups, the frequency of hepatomegaly was significantly higher in BA infants. The frequency of an abnormal shape or a noncontractile gallbladder was Table 1
Demographic, clinical, and laboratory data of the groups
studied Characteristics
BA (n = 137)
Non-BA (n = 10)
P-value
Age (days) (mean ± SD) Males [n (%)] Clay stool [n (%)] Bleeding tendency [n (%)] Growth failure [n (%)] Total bilirubin (mg/dl) (mean ± SD) Direct bilirubin (mg/dl) (mean ± SD) Alanine transaminase (U/l) (mean ± SD) Aspartate transaminase (U/l) (mean ± SD) Albumin (g/dl) (mean ± SD) Alkaline phosphatase (U/l) (mean ± SD) Gammaglutamyl transpeptidase (U/l) (mean ± SD) International normalized ratio (mean ± SD)
65.49 ± 25.17 62 (45.3) 122 (89.1) 10 (7.3) 11 (8) 11.73 ± 4.02
71.1 ± 12.49 7 (70) 10 (100) 1 (10) 1 (10) 10.18 ± 3.06
0.208 0.13 0.544 0.754 0.826 0.321
BA, biliary atresia.
7.91 ± 3.01
7.33 ± 2.1
0.698
152.4 ± 123.88
220.5 ± 125.48
0.018
243.82 ± 174.62
255.9 ± 102.17
0.27
3.3 ± 0.52 531.2 ± 318.16
3.22 ± 0.3 658.7 ± 297.55
0.634 0.095
584.1 ± 420.59
502.5 ± 266.71
0.803
1.05 ± 0.11
0.645
1.06 ± 0.1
In infants with cholestatic jaundice, the major diagnostic challenge is to distinguish medical causes such as infectious, metabolic, and genetic disorders from the surgical conditions such as BA and choledochal cyst. An early diagnosis of BA is essential for successful surgical correction by hepatic portoenterostomy [9]. To definitively exclude BA, the surgeon must observe patency of the biliary system with excretion into the duodenum. The traditional approach is to perform laparotomy and IOC, and to proceed with immediate portoenterostomy if BA is confirmed. Unfortunately, some infants with cholestatic jaundice may be misdiagnosed and will be subjected to a potentially negative surgical exploration [7]. The current study showed that 10 (6.8%) infants were misdiagnosed with BA. They all had clay stool. They had elevated GGT levels, normal international normalized ratio, and ultrasonographic and histopathological features that are associated commonly with BA, such as abnormal gallbladder contractility and ductular proliferation. Table 2
Ultrasonographic findings in the studied groups N (%)
Characteristics Hepatomegaly Spleen Splenomegaly Polyspenia Ascites Minimal Mild Moderate TC-sign GB contractility Contractile GB Abnormal GB (total) Noncontractile Rudimentary/nonvisualized
BA (n = 137)
Non-BA (n = 10)
P-value
129 (94.2)
7 (70)
0.005 0.553
86 4 16 11 4 1 23
(62.8) (2.9) (11.7) (8) (2.9) (0.7) (16.8)
5 (50) 0.0 0.0 – – – 0 (0.0)
9 128 75 53
(6.6) (93.4) (54.7) (38.7)
6 4 2 2
(60) (40) (20) (20)
0.252
0.158 < 0.0001
BA, biliary atresia; GB, gallbladder; TC, triangular cord.
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Misdiagnoses of BA Sira et al. 1303
Table 3
Histopathological findings in the studied groups
infection in infants with cholestasis should not exclude the possibility of BA [19].
N (%)
Characteristics Ductular proliferation Bile plugs Intracellular bile pigments Multinucleated giant hepatocytes Grade of portal fibrosis Absent/fibrous expansion of some portal tracts Fibrous expansion of most portal tracts Focal portoportal bridging Marked bridging Cirrhosis Portal cellular infiltrate Absent/minimal Mild Moderate/severe
BA (n = 137) 130 112 124 31
(94.9) (81.8) (90.5) (22.6)
Non-BA (n =10) 7 7 8 6
(70) (70) (80) (60)
4 (2.9)
3 (30)
42 (30.7)
2 (20)
59 (43.1) 24 (17.5) 5 (5.8)
3 (30) 2 (20) 0 (0.0)
73 (53.3) 38 (27.7) 26 (19)
3 (30) 4 (40) 3 (30)
P-value 0.003 0.361 0.289 0.009 0.003
0.360
BA, biliary atresia.
Our results showed that ALT was significantly higher in the non-BA group and the frequency of hepatomegaly was significantly higher in the BA group, whereas there was no statistically significant difference in the other clinical findings and laboratory measures in the form of total and direct bilirubin, and GGT level. In contrast to our results, Sun et al. [10] reported that GGT was significantly higher in those with BA than in those misdiagnosed with BA. In addition, although abnormal gallbladder contractility, ductular proliferation, and advanced grades of portal fibrosis were associated significantly with BA, yet, they were found in a considerable percentage of the non-BA groups (40, 70, and 50% respectively). This overlap may be the reason for misdiagnosis. In the current study, two of the non-BA infants received the final diagnosis of cytomegalovirus (CMV) hepatitis on the basis of positive CMV immunoglobulin M, positive CMV-DNA by PCR, absence of other etiologies, and the presence of a suggestive pathological picture of giant cell hepatitis as the classic inclusion bodies are rarely observed in neonatal infection [11]. Ozkan et al. [12] found inclusion bodies in one out of seven infants with neonatal CMV hepatitis. Moreover, despite the documentation of a CMV infection on the initial assessment, we proceeded with exclusion of BA by IOC. Although CMV hepatitis is easy to diagnose in most cases, some may present with cholestasis and clay stool, which was the case in our patients. This presentation needs to be differentiated from BA [13]. Furthermore, the association between BA and CMV has been investigated and described by different groups [14–16]. It was reported that prenatally acquired CMV infection in twins was associated temporally with a discordant development of neonatal hepatitis and BA [17]. In addition, CMV hepatitis may proceed to advanced hepatic fibrosis and even cirrhosis [18]. For this, the establishment of CMV
We found that ductular proliferation and advanced grades of portal fibrosis were significantly higher in the BA group than in the non-BA group. Similarly, Russo et al. [20] reported that higher grades of portal fibrosis and bile ductular proliferation showed the greatest difference between BA and non-BA groups. Moreira et al. [21] reported that only advanced fibrosis was significantly higher in the BA group than in other nonobstructive cholestasis, but early stages of portal fibrosis were comparable in both groups. Furthermore, portal fibrosis with early cirrhosis was found to be associated not only with BA but also with choledochal cyst, metabolic disorders, and some cases of PFIC [22]. PFIC is an autosomal recessive liver disorder characterized by an intrahepatic cholestasis because of bile canalicular transport defects. It is subdivided into three types with slightly different clinical, biochemical, and histopathological features. In the current study, PFIC type 3 was diagnosed in three of the non-BA infants. The diagnosis was made on the basis of a constellation of phenotypic features including elevated serum bile acids among other biochemical parameters, and negative immunostaining for multidrug resistance protein 3 in liver biopsy [23] and prurits, which appeared at a later follow-up. Pale stool may be an associated symptom with jaundice, dark urine, and hepatosplenomegaly, confusing the condition with BA [24]. Histologically, portal fibrosis and ductular proliferation with a mixed inflammatory infiltrate are the main characteristics of PFIC type 3 [25]. Although elevated GGT has been described as a feature of BA, in infants with Alagille syndrome, the total and conjugated bilirubin and GGT are quite elevated [26]. Discrimination from BA is very important, but can be difficult, particularly from the syndromic type of BA, which is associated with other anomalies such as congenital cardiac disease. In general, liver biopsy can discriminate BA (with bile duct proliferation) from Alagille syndrome (with bile duct paucity), but in younger infants, there is a considerable overlap of the histologic pattern, with bile duct proliferation being common in Alagille syndrome infants younger than 6 months of age, making it difficult to discriminate it from BA [27]. One of the non-BA infants was diagnosed with Alagille syndrome. We based our diagnosis of Alagille syndrome on the presence of intrahepatic bile duct paucity on a followup liver biopsy, in association with the characteristic facial features, cardiac anomaly, and posterior embryotoxon [26]. In infants with Alagille syndrome, interlobular bile ducts may be present early in the course of the disorder, but not in later follow-up biopsies. Less frequently, bile ductular proliferation with associated portal inflammation may be present. The latter finding may lead to a misdiagnosis of
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BA. An additional histologic pattern that may be noted in infants with Algille syndrome is giant cell hepatitis [28]. Giant cell is one of the features of INH. Three infants in our study received the diagnosis of INH. The clinical presentations of cholestasis in infancy caused by neonatal hepatitis and BA are very similar. Diagnosis may be difficult on many occasions. Stool color and the onset of jaundice could not differentiate severe neonatal hepatitis from BA. In a study by Lai et al. [29], although no BA was missed, four cases of neonatal hepatitis were misdiagnosed as BA, resulting in unnecessary laparotomy. Furthermore, Aktas et al. [30] reported that quantitative analysis of proliferating ductules and proliferation activity of ductal epithelial cells may be helpful in the differential diagnosis of neonatal hepatitis and BA. In the current study, the diagnosis of INH was made by exclusion when a cause of NC could not be elucidated after extensive investigations [31], besides the presence of giant cell hepatitis [32]. Ductal plate malformation may be found in liver biopsy of infants with BA [33]. Congenital hepatic fibrosis (CHF) is a developmental malformation found in fibrocystic diseases of the liver and represents ductal plate malformation of interlobular bile ducts [34]. Four clinical forms of CHF have been described: portal hypertensive, cholangitic, mixed portal hypertensive-cholangitic, and latent forms [35]. One of the non-BA infants in our study was diagnosed with a cholangitic form of CHF. Grossly, the liver is generally enlarged and extremely firm with fibrotic cut surfaces. Diffuse periportal fibrosis is a common histologic feature. Marked neutrophilic infiltration involving the bile ducts and fibrous bands is a feature of the cholangitic form. Microabscess formation resulting from duct rupture can occur in the cholangitic form, which may lead to difficulty in differentiating this form of CHF from extrahepatic biliary obstruction with ascending infection [36]. We established our diagnosis by the presence of the pathological features found in the followup liver biopsy that was taken intraoperatively. The portal tracts were enlarged and linked by broad fibrous bands, which were separate from the hepatic parenchyma and contain irregular cysts lined by biliary epithelial cells with coexistent cholangitis. The presence of these features with the presence of cholestasis defined the cholangitic form of CHF [37].
necessity of the awareness of this group of diseases. In addition, a meticulous preoperative workup should be performed to exclude other causes of NC even if signs of BA are present, especially if features such as giant cells in histopathology are present. This involves completing the NC workup in parallel with all common causes of NC at one go rather than in series to prevent loss of valuable time and efforts.
Acknowledgements The authors thank the resident physicians and nursing staff of the Pediatric Hepatology Department for their kind help. This study was funded by the National Liver Institute, Menofiya University, Egypt, without any particular role in the study design, data collection, and analysis or the writing of the report. Conflicts of interest
There are no conflicts of interest.
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In conclusion, the current study showed that certain causes of NC may still be misdiagnosed as BA even after extensive preoperative workup. The ultimate goal is to prevent misdiagnosis. Targeting the same goal, the current study highlights the parameters that may lead to a misdiagnosis of BA in an attempt to avoid this in the future. The criteria usually used to discriminate BA (such as clay stool, abnormal gallbladder, ductular proliferation, and advanced portal fibrosis) were also found, substantially, in the misdiagnosed patients. This raises the
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Common misdiagnoses of biliary atresia Mostafa M. Siraa, Mohammad Tahab and Ahmad M. Siraa Objectives Discrimination of biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. We aimed to analyze the clinicopathological findings in cholestatic infants who were provisionally diagnosed with BA and then excluded by intraoperative cholangiography compared with those with a definitive diagnosis of BA and to shed light on common misdiagnoses of BA. Methods We retrospectively analyzed the data of infants diagnosed preoperatively with BA and referred to surgery between the years 2009 and 2013. On the basis of intraoperative cholangiography results, infants were divided into those with a definitive diagnosis of BA and those misdiagnosed with BA. Results Out of 147 infants, there was a misdiagnosis of BA in 10 (6.8%) infants. Alanine transaminase was significantly higher in the non-BA group, whereas other clinical and laboratory findings were comparable in both groups. Hepatomegaly and abnormal gallbladder in ultrasound, and ductular proliferation and advanced grades of portal fibrosis in liver biopsy were significantly higher in infants with BA. However, giant cells were more common in the non-BA infants. Nonetheless, the frequency of clay stool, hepatomegaly, abnormal gallbladder, ductular proliferation, and advanced portal fibrosis was remarkable (100, 70, 40,
Introduction Biliary atresia (BA) is the most common cause of chronic cholestasis in neonates and infants. It constitutes nearly one-third of all neonatal cholestasis (NC) and more than 90% of obstructive cholestatic cases [1]. BA is a destructive inflammatory obliterative cholangiopathy that affects varying lengths of both intrahepatic and extrahepatic bile ducts [2]. If untreated, BA leads to cirrhosis, hepatic failure, and death within the first 2 years of life [3]. The diagnosis of BA, particularly distinguishing it from other causes of liver injury in the neonatal period, is challenging as there is a high degree of overlap in the clinical, biochemical, imaging, and histopathological characteristics of BA and other causes of NC [4]. There is no single preoperative investigation that enables the diagnosis of BA to be made with certainty [5]. The histopathological features can overlap with other pediatric cholestatic liver diseases. In some cases, specimen interpretation is complicated by equivocal histopathological findings or atypical clinical and radiological findings [4]. The most useful distinguishing histopathological feature in BA is the portal fibrosis and bile duct proliferation; nonetheless, a similar pattern may be found in 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
70, and 50%, respectively) in the misdiagnosed infants. The misdiagnoses were idiopathic neonatal hepatitis, progressive familial intrahepatic cholestasis type 3, cytomegalovirus hepatitis, Alagille syndrome, and a cholangitic form of congenital hepatic fibrosis. Conclusion A meticulous preoperative workup should be performed to exclude other causes of NC even if signs of BA are present, especially if features such as giant cells in histopathology are present. This involves completing the NC workup in parallel involving all common causes of NC rather than performing them in series to avoid loss of valuable time and efforts. Eur J Gastroenterol Hepatol 26:1300–1305 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:1300–1305 Keywords: biliary atresia, intraoperative cholangiography, liver biopsy, misdiagnoses, neonatal cholestasis Departments of aPediatric Hepatology and bHepatobiliary Surgery, National Liver Institute, Menofiya University, 32511, Shebin El-koom, Menofiya, Egypt Correspondence to Mostafa M. Sira, MD, Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt Tel: + 20 48 222 2740; fax: + 20 48 223 4586; e-mail: [email protected] Received 14 March 2014 Accepted 28 July 2014
other causes of nonobstructive cholestasis such as alpha 1 antitrypsin deficiency disease, cystic fibrosis, and progressive familial intrahepatic cholestasis (PFIC) type 3 [6]. A constellation of clinical, laboratory, and ultrasonographic findings raises the suspicion of BA, which is supported by features of biliary outflow obstruction in liver biopsy and confirmed by laparotomy or intraoperative cholangiography (IOC) before surgery. Some infants may exhibit patent biliary tree, BA is then excluded [7]. The aim of this retrospective study was to analyze the clinicopathological findings in cholestatic infants who were provisionally diagnosed with BA and then excluded by IOC compared with those in infants with a definitive diagnosis of BA and to shed light on certain etiologies that can, still, be misdiagnosed as BA despite an extensive preoperative diagnostic workup in specialized tertiary centers.
Patients and methods Study population
This retrospective study included 147 infants with cholestasis attending the Pediatric Hepatology Department DOI: 10.1097/MEG.0000000000000198
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Misdiagnoses of BA Sira et al. 1301
in the period between year 2009 and 2013, who were provisionally diagnosed with BA. They were referred to the Department of Hepatobiliary Surgery, National Liver Institute, for Kasai portoenterostomy. According to the results of laparotomy and IOC, infants were divided into two groups. The first group (BA group) included infants with a definitive diagnosis of BA. The second group (non-BA cholestasis group) included cholestatic infants in whom BA was ruled out by confirming the patent biliary system by IOC.
Statistical analysis
Descriptive results were expressed as mean ± SD or number (percentage) of individuals with a condition. For quantitative data, statistical significance between individual groups was tested using the Mann–Whitney U nonparametric test. For qualitative data, significance between groups was tested using the χ2-test. Results were considered significant if P-value was up to 0.05. Statistical analysis was carried out using SPSS, version 13 (SPSS Inc., Chicago, Illinois, USA).
Data collection
Preoperative demographic (age and sex), clinical and laboratory data including total and direct bilirubin, transaminases [alanine transaminase (ALT) and aspartate transaminase], biliary enzymes [gammaglutamyl transpeptidase (GGT) and alkaline phosphatase], total proteins, serum albumin, and international normalized ratio were determined. Ultrasonographic findings in the form of liver and spleen size, ascites, contractility of gallbladder, and triangular cord sign were all listed. Contractile gallbladder was defined by the change in gallbladder dimensions on ultrasonography 30 min postprandial compared with its basal size after 4 h of fasting. The gallbladder was considered abnormal if no change of its dimensions was observed, if its length was less than 20.5 mm [5], or if it was not visualized [8]. Hepatic histopathological features in the form of portal fibrosis, ductular proliferation, bile plugs, intracellular cholestasis, portal cellular infiltrate, and multinucleated giant hepatocyte were also revised. The study was approved by the Research Ethics Committee of the National Liver Institute, Menofiya University, Egypt.
Results Population characteristics
Out of the 147 infants, there was a misdiagnosis of BA in 10 cases, with an overall misdiagnosis rate of 6.8% in a 5-year period. BA was excluded on the basis of IOC showing a patent biliary system (Fig. 1). The mean age of infants in the BA group was 65.49 ± 25.17 days and that of the infants in the non-BA group was 71.1 ± 12.49 days, with no significant statistical difference (P = 0.208). There were 62 male infants (45.3%) in the BA versus seven male infants (70%) in the non-BA group (P = 0.13). Idiopathic neonatal hepatitis (INH) and PFIC type 3 were found in the majority (60%) of the infants in the non-BA group (Fig. 2).
Fig. 1
Intraoperative cholangiography
Traditionally, the operation is performed under general anesthesia, where the patient lies in the supine position and a small right upper abdominal quadrant transverse or oblique incision is made. The abdomen is explored; if no gallbladder or a fibrotic gallbladder and/or atretic extrahepatic biliary tree are present, no cholangiogram is performed and Kasai portoenterostomy is performed. If a gallbladder is visualized and is patent, an operative cholangiogram is the next maneuver, wherein the tip of the gallbladder is cannulated with a 24 G intravenous cannula and a burse string is taken around its entrance to prevent the leak of the contrast (Urografin 76%; BerliMed S.A., Madrid, Spain or Ultravist; Bayer HealthCare Pharmaceuticals Inc., Berlin, Germany), which is instilled under fluoroscopy (Philips BV 25 gold C-Arm; Philips Medical Systems, Eindhoven, The Netherlands). If the contrast flows into the duodenum and into the intrahepatic bile ducts, BA is ruled out. At that time, a wedge liver biopsy is performed, the catheter is removed, and the incision is closed.
Nati Ins
PHILIPS BV25 gold
6 3 2 4 1
5 c
Intraoperative cholangiography. A case of non-BA where the contrast introduced through the cannula (1) flows from the gallbladder (2) to the cystic duct (3), then into the duodenum (4) through the common bile duct, which was then clamped by bulldog forceps, (5) to reveal the patency of common hepatic and right and left hepatic ducts (6). BA, biliary atresia.
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1302 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
significantly higher in BA than that in non-BA infants, whereas there was no statistically significant difference between both groups in other parameters such as splenomegaly, ascites, and triangular cord sign. The occurrence of polyspenia was only found in BA infants (Table 2).
Fig. 2
CHF 1 (10%)
AGS 1 (10%)
INH 3 (30%)
CMV 2 (20%)
Histopathological features
PFIC3 3 (30%)
Misdiagnoses of biliary atresia. AGS, Alagille syndrome (n = 1); CHF, congenital hepatic fibrosis – cholangitic type (n = 1); CMV, cytomegalovirus hepatitis (n = 2); INH, idiopathic neonatal hepatitis (n = 3); PFIC3, progressive familial intrahepatic cholestasis type 3 (n = 3).
Ductular proliferation and advanced grades of portal fibrosis were significantly higher in the BA group than that in the non-BA group (P = 0.003 for both), whereas multinucleated giant hepatocytes were significantly higher in the non-BA than in the BA group (P = 0.009). There was no statistically significant difference between both groups in bile plugs, intracellular bile pigments, or portal cellular infiltrate (Table 3).
Discussion Clinical and laboratory findings
The clinical presentation of all the infants that first attracts attention was jaundice and clay stool in the majority of cases. There was no statistically significant difference in the clinical findings and laboratory parameters between the BA and the non-BA infants, except for ALT, which was significantly higher in non-BA infants (220.5 ± 125.48 vs. 152.4 ± 123.88; P = 0.018) (Table 1). Ultrasonographic parameters
On comparing the ultrasonographic findings between both groups, the frequency of hepatomegaly was significantly higher in BA infants. The frequency of an abnormal shape or a noncontractile gallbladder was Table 1
Demographic, clinical, and laboratory data of the groups
studied Characteristics
BA (n = 137)
Non-BA (n = 10)
P-value
Age (days) (mean ± SD) Males [n (%)] Clay stool [n (%)] Bleeding tendency [n (%)] Growth failure [n (%)] Total bilirubin (mg/dl) (mean ± SD) Direct bilirubin (mg/dl) (mean ± SD) Alanine transaminase (U/l) (mean ± SD) Aspartate transaminase (U/l) (mean ± SD) Albumin (g/dl) (mean ± SD) Alkaline phosphatase (U/l) (mean ± SD) Gammaglutamyl transpeptidase (U/l) (mean ± SD) International normalized ratio (mean ± SD)
65.49 ± 25.17 62 (45.3) 122 (89.1) 10 (7.3) 11 (8) 11.73 ± 4.02
71.1 ± 12.49 7 (70) 10 (100) 1 (10) 1 (10) 10.18 ± 3.06
0.208 0.13 0.544 0.754 0.826 0.321
BA, biliary atresia.
7.91 ± 3.01
7.33 ± 2.1
0.698
152.4 ± 123.88
220.5 ± 125.48
0.018
243.82 ± 174.62
255.9 ± 102.17
0.27
3.3 ± 0.52 531.2 ± 318.16
3.22 ± 0.3 658.7 ± 297.55
0.634 0.095
584.1 ± 420.59
502.5 ± 266.71
0.803
1.05 ± 0.11
0.645
1.06 ± 0.1
In infants with cholestatic jaundice, the major diagnostic challenge is to distinguish medical causes such as infectious, metabolic, and genetic disorders from the surgical conditions such as BA and choledochal cyst. An early diagnosis of BA is essential for successful surgical correction by hepatic portoenterostomy [9]. To definitively exclude BA, the surgeon must observe patency of the biliary system with excretion into the duodenum. The traditional approach is to perform laparotomy and IOC, and to proceed with immediate portoenterostomy if BA is confirmed. Unfortunately, some infants with cholestatic jaundice may be misdiagnosed and will be subjected to a potentially negative surgical exploration [7]. The current study showed that 10 (6.8%) infants were misdiagnosed with BA. They all had clay stool. They had elevated GGT levels, normal international normalized ratio, and ultrasonographic and histopathological features that are associated commonly with BA, such as abnormal gallbladder contractility and ductular proliferation. Table 2
Ultrasonographic findings in the studied groups N (%)
Characteristics Hepatomegaly Spleen Splenomegaly Polyspenia Ascites Minimal Mild Moderate TC-sign GB contractility Contractile GB Abnormal GB (total) Noncontractile Rudimentary/nonvisualized
BA (n = 137)
Non-BA (n = 10)
P-value
129 (94.2)
7 (70)
0.005 0.553
86 4 16 11 4 1 23
(62.8) (2.9) (11.7) (8) (2.9) (0.7) (16.8)
5 (50) 0.0 0.0 – – – 0 (0.0)
9 128 75 53
(6.6) (93.4) (54.7) (38.7)
6 4 2 2
(60) (40) (20) (20)
0.252
0.158 < 0.0001
BA, biliary atresia; GB, gallbladder; TC, triangular cord.
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Misdiagnoses of BA Sira et al. 1303
Table 3
Histopathological findings in the studied groups
infection in infants with cholestasis should not exclude the possibility of BA [19].
N (%)
Characteristics Ductular proliferation Bile plugs Intracellular bile pigments Multinucleated giant hepatocytes Grade of portal fibrosis Absent/fibrous expansion of some portal tracts Fibrous expansion of most portal tracts Focal portoportal bridging Marked bridging Cirrhosis Portal cellular infiltrate Absent/minimal Mild Moderate/severe
BA (n = 137) 130 112 124 31
(94.9) (81.8) (90.5) (22.6)
Non-BA (n =10) 7 7 8 6
(70) (70) (80) (60)
4 (2.9)
3 (30)
42 (30.7)
2 (20)
59 (43.1) 24 (17.5) 5 (5.8)
3 (30) 2 (20) 0 (0.0)
73 (53.3) 38 (27.7) 26 (19)
3 (30) 4 (40) 3 (30)
P-value 0.003 0.361 0.289 0.009 0.003
0.360
BA, biliary atresia.
Our results showed that ALT was significantly higher in the non-BA group and the frequency of hepatomegaly was significantly higher in the BA group, whereas there was no statistically significant difference in the other clinical findings and laboratory measures in the form of total and direct bilirubin, and GGT level. In contrast to our results, Sun et al. [10] reported that GGT was significantly higher in those with BA than in those misdiagnosed with BA. In addition, although abnormal gallbladder contractility, ductular proliferation, and advanced grades of portal fibrosis were associated significantly with BA, yet, they were found in a considerable percentage of the non-BA groups (40, 70, and 50% respectively). This overlap may be the reason for misdiagnosis. In the current study, two of the non-BA infants received the final diagnosis of cytomegalovirus (CMV) hepatitis on the basis of positive CMV immunoglobulin M, positive CMV-DNA by PCR, absence of other etiologies, and the presence of a suggestive pathological picture of giant cell hepatitis as the classic inclusion bodies are rarely observed in neonatal infection [11]. Ozkan et al. [12] found inclusion bodies in one out of seven infants with neonatal CMV hepatitis. Moreover, despite the documentation of a CMV infection on the initial assessment, we proceeded with exclusion of BA by IOC. Although CMV hepatitis is easy to diagnose in most cases, some may present with cholestasis and clay stool, which was the case in our patients. This presentation needs to be differentiated from BA [13]. Furthermore, the association between BA and CMV has been investigated and described by different groups [14–16]. It was reported that prenatally acquired CMV infection in twins was associated temporally with a discordant development of neonatal hepatitis and BA [17]. In addition, CMV hepatitis may proceed to advanced hepatic fibrosis and even cirrhosis [18]. For this, the establishment of CMV
We found that ductular proliferation and advanced grades of portal fibrosis were significantly higher in the BA group than in the non-BA group. Similarly, Russo et al. [20] reported that higher grades of portal fibrosis and bile ductular proliferation showed the greatest difference between BA and non-BA groups. Moreira et al. [21] reported that only advanced fibrosis was significantly higher in the BA group than in other nonobstructive cholestasis, but early stages of portal fibrosis were comparable in both groups. Furthermore, portal fibrosis with early cirrhosis was found to be associated not only with BA but also with choledochal cyst, metabolic disorders, and some cases of PFIC [22]. PFIC is an autosomal recessive liver disorder characterized by an intrahepatic cholestasis because of bile canalicular transport defects. It is subdivided into three types with slightly different clinical, biochemical, and histopathological features. In the current study, PFIC type 3 was diagnosed in three of the non-BA infants. The diagnosis was made on the basis of a constellation of phenotypic features including elevated serum bile acids among other biochemical parameters, and negative immunostaining for multidrug resistance protein 3 in liver biopsy [23] and prurits, which appeared at a later follow-up. Pale stool may be an associated symptom with jaundice, dark urine, and hepatosplenomegaly, confusing the condition with BA [24]. Histologically, portal fibrosis and ductular proliferation with a mixed inflammatory infiltrate are the main characteristics of PFIC type 3 [25]. Although elevated GGT has been described as a feature of BA, in infants with Alagille syndrome, the total and conjugated bilirubin and GGT are quite elevated [26]. Discrimination from BA is very important, but can be difficult, particularly from the syndromic type of BA, which is associated with other anomalies such as congenital cardiac disease. In general, liver biopsy can discriminate BA (with bile duct proliferation) from Alagille syndrome (with bile duct paucity), but in younger infants, there is a considerable overlap of the histologic pattern, with bile duct proliferation being common in Alagille syndrome infants younger than 6 months of age, making it difficult to discriminate it from BA [27]. One of the non-BA infants was diagnosed with Alagille syndrome. We based our diagnosis of Alagille syndrome on the presence of intrahepatic bile duct paucity on a followup liver biopsy, in association with the characteristic facial features, cardiac anomaly, and posterior embryotoxon [26]. In infants with Alagille syndrome, interlobular bile ducts may be present early in the course of the disorder, but not in later follow-up biopsies. Less frequently, bile ductular proliferation with associated portal inflammation may be present. The latter finding may lead to a misdiagnosis of
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BA. An additional histologic pattern that may be noted in infants with Algille syndrome is giant cell hepatitis [28]. Giant cell is one of the features of INH. Three infants in our study received the diagnosis of INH. The clinical presentations of cholestasis in infancy caused by neonatal hepatitis and BA are very similar. Diagnosis may be difficult on many occasions. Stool color and the onset of jaundice could not differentiate severe neonatal hepatitis from BA. In a study by Lai et al. [29], although no BA was missed, four cases of neonatal hepatitis were misdiagnosed as BA, resulting in unnecessary laparotomy. Furthermore, Aktas et al. [30] reported that quantitative analysis of proliferating ductules and proliferation activity of ductal epithelial cells may be helpful in the differential diagnosis of neonatal hepatitis and BA. In the current study, the diagnosis of INH was made by exclusion when a cause of NC could not be elucidated after extensive investigations [31], besides the presence of giant cell hepatitis [32]. Ductal plate malformation may be found in liver biopsy of infants with BA [33]. Congenital hepatic fibrosis (CHF) is a developmental malformation found in fibrocystic diseases of the liver and represents ductal plate malformation of interlobular bile ducts [34]. Four clinical forms of CHF have been described: portal hypertensive, cholangitic, mixed portal hypertensive-cholangitic, and latent forms [35]. One of the non-BA infants in our study was diagnosed with a cholangitic form of CHF. Grossly, the liver is generally enlarged and extremely firm with fibrotic cut surfaces. Diffuse periportal fibrosis is a common histologic feature. Marked neutrophilic infiltration involving the bile ducts and fibrous bands is a feature of the cholangitic form. Microabscess formation resulting from duct rupture can occur in the cholangitic form, which may lead to difficulty in differentiating this form of CHF from extrahepatic biliary obstruction with ascending infection [36]. We established our diagnosis by the presence of the pathological features found in the followup liver biopsy that was taken intraoperatively. The portal tracts were enlarged and linked by broad fibrous bands, which were separate from the hepatic parenchyma and contain irregular cysts lined by biliary epithelial cells with coexistent cholangitis. The presence of these features with the presence of cholestasis defined the cholangitic form of CHF [37].
necessity of the awareness of this group of diseases. In addition, a meticulous preoperative workup should be performed to exclude other causes of NC even if signs of BA are present, especially if features such as giant cells in histopathology are present. This involves completing the NC workup in parallel with all common causes of NC at one go rather than in series to prevent loss of valuable time and efforts.
Acknowledgements The authors thank the resident physicians and nursing staff of the Pediatric Hepatology Department for their kind help. This study was funded by the National Liver Institute, Menofiya University, Egypt, without any particular role in the study design, data collection, and analysis or the writing of the report. Conflicts of interest
There are no conflicts of interest.
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In conclusion, the current study showed that certain causes of NC may still be misdiagnosed as BA even after extensive preoperative workup. The ultimate goal is to prevent misdiagnosis. Targeting the same goal, the current study highlights the parameters that may lead to a misdiagnosis of BA in an attempt to avoid this in the future. The criteria usually used to discriminate BA (such as clay stool, abnormal gallbladder, ductular proliferation, and advanced portal fibrosis) were also found, substantially, in the misdiagnosed patients. This raises the
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