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Biliary Atresia: A Challenging Diagnosis Mostafa Mohamed Sira*, Tahany Abdel-Hameed Salem and Ahmad Mohamed Sira Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt Abstract: Biliary atresia (BA) constitutes about one third of all neonatal cholestasis (NC) and the most common indication (up to 50%) of liver transplantation (LTx) in children. Despite extensive studies, its etiopathogenesis has not been clearly revealed. Treatment is primarily surgical based on reinstitution of bile flow by Kasai portoenterostomy, the success of which is largely dependent on the early diagnosis before 60 days of age. If portoenterostomy is not successful or not performed, LTx is the only life-saving alternative. Accurate 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 clinical, biochemical, imaging, and histological characteristics. There is no single preoperative investigation that enables the diagnosis of BA to be made with certainty. Liver biochemistry assessment, biliary radionuclide excretion scanning, magnetic resonance cholangiopancreatography (MR), endoscopic retrograde cholangiopancreatography (ER), percutaneous needle liver biopsy, and laparoscopy can all be helpful, but their results are not individually diagnostic. The current review presents an overview of BA with emphasis on the recent diagnostic modalities.

Keywords: Biliary atresia, diagnosis, Doppler, liver biopsy, neonatal cholestasis, ultrasound. 1. DEFINITION Biliary atresia (BA) is an idiopathic progressive inflammatory process of the extrahepatic bile ducts with obliteration and concomitant ongoing damage of the intrahepatic bile ducts resulting in chronic cholestasis, progressive fibrosis, and eventually biliary cirrhosis [1]. 2. EPIDEMIOLOGY Although the incidence of BA is approximately 5 to 32 cases per 100,000 live births, it constitutes nearly one third of all NC cases [2]. The reported incidence is highest in Asia and the Pacific region [3]. The estimates in Taiwan and Japan range from 1.1 to 3.7 cases per 10,000 live births [4, 5], while it occurs in approximately 1 in 18,000 in Western Europe [3]. In the United States, BA occurs with an estimated frequency of 1 in 8000 to 15,000 live births, resulting in 250 to 400 new cases per year [6]. Females are affected slightly more often than males [3]. Some studies of time- and space-time distribution of BA have suggested seasonal variation and clustering of cases [7]. 3. CLASSIFICATION Clinically, BA is classified into two types, perinatal and embryonic. Perinatal, (acquired, or non-syndromic) form of BA; s for approximately 90% of affected infants. Patients with this type are asymptomatic, anicteric at birth, and develop jaundice in the first postnatal weeks. These infants are otherwise healthy

and appear to suffer from a perinatal insult that leads to biliary obstruction [8]. Embryonic (syndromic) form of BA; patients with this type have no jaundice-free interval and suffer from one or more congenital anomalies, such as interruption of the suprarenal segment of the inferior vena cava with azygous continuation, preduodenal portal vein, midline symmetric liver, intestinal malrotation, situs anomalies, bronchial anomalies, and polysplenia or asplenia. The embryonic form thus appears to be caused by a developmental abnormality of the biliary tree and includes those infants with the biliary atresia splenic malformation (BASM) syndrome [9]. Surgical (Anatomical) types of BA are classified on anatomical basis, referring to the level and severity of the obstruction. The most commonly used Japanese classification describes 3 main types (Figure 1). Type I, atresia of the common bile ducts with patent gallbladder (GB) and hepatic ducts (i.e. “distal” BA). Type II, atresia of the common hepatic ducts with patent right and the left hepatic ducts (i.e., “proximal” BA). Type II is subgrouped into two subtypes. Type IIa, where the GB, cystic duct and common bile ducts are patent (sometimes with a cyst in the hilum, i.e., “cystic BA”). Type IIb; with the cystic, common bile duct and common hepatic duct are all obliterated. Type III; is characterized by atresia of the entire extrahepatic biliary tree (i.e., “complete” BA) [10]. Most often, BA is complete (type III, 73%) or subcomplete (type IIb, 18%), with “cystic” BA and “distal” BA being infrequent (types IIa and I, 6% and 3%, respectively) [11]. 4. ETIOLOGY AND PATHOGENESIS

*Address correspondence to this author at the Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom, Menofiya, Egypt; Tel: +2-048-222-2740; Fax: +2-048-223-4586; E-mail: [email protected] E-ISSN: 2308-6483/13

The basic etiology of BA is still not clear [1]. The suspected causes generally fall into infection or © 2013 Synergy Publishers

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familial cases have been reported [3]. It was reported that about 20% of patients with BA have non-hepatic congenital anomalies, including situs anomalies in 8%. The increased incidence of non-hepatic anomalies in patients with BA and the genetic mutations reported in subsets of patients with laterality defects suggest that multiple genes are involved [9]. Mutations in the JAGGED1 gene; which are associated with Alagille syndrome, have been found in about 10% of patients with BA [12] suggesting that JAGGED1 could be a modifying factor in patients with BA [13].

Figure 1: Schematic illustration of biliary atresia classification. Illustration by Mostafa Sira, Department of Pediatric Hepatology, National Liver Institute, Menofiya University. GB: gallbladder; HD: hepatic duct; CHD: common hepatic duct; CD: cystic duct; CBD: common bile duct.

autoimmune-/immune-mediated categories, with the possibility of inherited predispositions [12]. It was proposed that BA was the result of a “multihit” pathologic process, in which a viral or toxic insult to biliary epithelium leads to newly expressed or altered antigens on the surface of bile duct epithelia. These antigens are presented by macrophages to T lymphocytes. Cytotoxic T cells then elicit a T helper-1 cellular response causing bile duct epithelial injury, eventually, resulting in fibrosis and occlusion of the extrahepatic bile ducts [13]. 4.1. The Infectious Causes It was suggested that BA is caused by an immune response to an unknown triggering event. As a potential initiator of this immune process, a viral infection has been considered. This hypothesis has been ed by findings of individual viral strains in BA patients [14]. It was also ed by the observation that all livers of BA patients stained positive for Mx protein (a myxovirus resistance protein) and toll-like receptor, both of which are markers known to be up-regulated during viral infections [15]. Different viral agents have been associated with BA; such as cytomegalovirus (CMV), human papilloma virus, reovirus, and rotavirus [16, 17]. In contrast, no association with hepatitis A, B and C viruses has been found [18]. 4.2. Genetic Causes Several observations suggest that a genetic component plays a role in the pathogenesis of BA as

By analyzing the phenotype of hepatocyte nuclear factor 6 (Hnf6)-knocked out mice, the GB was absent, the extrahepatic bile ducts were abnormal, and the development of the intrahepatic bile ducts was perturbed in the prenatal period [19]. Moreover, mutations in genes coding for alanine-glyoxylate aminotransferase [20], X-prolyl aminopeptidase P and adducin 3 genes [21] have also been linked to the occurrence of BA. 4.3. Defective Morphogenesis Several lines of evidence suggest that fetal form of BA is caused by defective morphogenesis of the biliary tree. Because anomalies of visceral organ symmetry (polysplenia syndrome) are associated with BA, it is of interest that a recessive insertional mutation in the proximal region of mouse chromosome 4 or complete deletion of the inversion (INV) gene in the mouse leads to anomalous development of the hepatobiliary system in this model [13]. 4.4. Immunologic Causes The immune response has received the most attention in human based studies of BA pathogenesis [22]. Genes that encode a variety of immune regulatory proteins, in part, control the susceptibility of immune or autoimmune injury to biliary epithelia [23, 24]. +

+

The infiltration of CD4 and CD8 T lymphocytes and macrophages has been consistently observed in the periductal space or along the duct epithelium in conjunction with increased expression of cytokines + [25]. Davenport et al., [14] demonstrated that CD4 T + lymphocytes and natural killer (CD56 ) cells predominated in the liver and extrahepatic bile duct of patients with BA, and that intercellular adhesion molecule-1 was expressed in sinusoidal endothelium. Ghonein et al., [26] demonstrated that hepatic expression of intercellular adhesion molecule-1 was

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significantly higher in BA compared to other cholestatic disorders in neonates. Moreover, Sira et al., [27] reported that CD56 expressed on the majority of biliary epithelial cells but not in other neonatal cholestatic disorders. 4.5. Autoimmunity in BA BA shares features with several autoimmune diseases, such as the female predominance, apparent triggering by viral infection, and aberrant major histocomptability expression in bile duct epithelium. Consequently, it has been proposed that tissue injury in patients with BA may represent an autoimmunemediated process. Some patients with BA were positive for serum immunoglobulin G and antineutrophil cytoplasmic antibodies, with higher levels of the antineutrophil cytoplasmic antibodies compared with children and adults with other liver diseases [13]. 4.6. Vascular Etiology An ischemic etiology for BA has been proposed based on direct experimental evidence [28]. Intrahepatic and extrahepatic bile ducts receive their blood supply exclusively from the hepatic arterial circulation [13]. Several investigators have demonstrated an arteriopathy in branches of the hepatic artery of the extrahepatic biliary tree of patients with BA. It has been proposed that the vasculopathy may be the primary lesion in patients with BA [29]. 4.7. Ductal Plate Malformation Ductal plate malformation (DPM) is one of the etiologic theories for the development of BA. It is a possible primary factor in the pathogenesis of BA causing defects in development of the intra hepatic bile ducts, and this has been clinically observed in some patients. This maldevelopment is thought to occur by failure of the remodeling process of ductal plate structures between 11 and 13 weeks of gestation [12]. Abnormal remodeling leads to DPM that is believed to be responsible for the liver lesion of congenital hepatic fibrosis and other bile duct dysplasias. A number of infants with BA show evidence of DPM on liver biopsy [30]. 4.8. Maternal Microchimerism Maternal microchimerism occurs when a small number of maternal cells are transferred to the offspring during pregnancy. This is known to occur in up to 40% of normal pregnancies. Maternal-fetal

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lymphocytic transfer is known to occur during pregnancy starting as early as the tenth week of gestation and continuing up to delivery [31]. + Significantly larger numbers of maternal XX cells, + + CD8 T cells, CD45 cells, and cytokeratin-positive cells were found in the portal area and sinusoids of patients with BA in comparison with control patients suggesting that maternal immunologic insults represent the underlying pathogenesis in BA [32]. 4.9. Toxin Exposure Time and space clustering of cases of BA have led to the proposal that an environmental toxin could be involved in its pathogenesis. Currently, other than infectious agents, no environmental agent has been clearly associated with BA in humans. Two outbreaks of BA in lambs and calves in Australia may have been related to a fungal or other environmental toxin exposure [13]. Other observations suggested the presence of a phytotoxin or mycotoxin that could insult the fetal hepatobiliary tree [33]. 5. CLINICAL FEATURES Infants with cholestasis may present with prolonged conjugated hyper-bilirubinemia, age of dark urine with or without pale (acholic or clay-colored) stools [34]. Intrahepatic and extrahepatic forms of cholestasis share numerous clinical and biochemical features and no clinical symptom is pathognomonic of each [35]. After birth, the clinical features of BA is jaundice (conjugated hyper-bilirubinemia lasting beyond two weeks of life), acholic stools, dark urine and hepatomegaly [3]. The general condition of the child is usually good. There is no failure to thrive, at least in the first months. Thereafter, weight loss and irritability develop, accompanied by increasing levels of jaundice. Later signs include splenomegaly (suggesting portal hypertension), ascites and hemorrhage (which can be intracranial, gastrointestinal or from the umbilical stump) due to impaired absorption of vitamin K. If untreated, this condition leads to cirrhosis and death within the first years of life [3]. In our experience, intracranial hemorrhage may be the initial presentation even before the appearance of jaundice. 6. EVALUATION OF BA There are some obstacles that make an early diagnosis of BA challenging. First, despite the need for

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early surgical intervention in this disease, there is a general lack of understanding of the importance of early identification among health care providers. Few primary care physicians see more than 1 or 2 cases of BA during their careers, whereas unconjugated hyperbilirubinemia is extremely common, particularly among breast-fed infants [36]. A second obstacle is the lack of convenient methods of screening. The efficacy of stool color cards and conjugated bilirubin testing were evaluated in Europe and Asia [4, 37-39]. A third obstacle is that the jaundiced infant may not be seen at the optimal time for identification of BA. The unconjugated hyperbilirubinemia, due to breast feeding in the first 2-3 weeks of life, may obscure the conjugated hyperbilirubinemia of BA making it appear that jaundice is actually improving. As the indirect bilirubin falls during the first month of life in an infant with BA who is also breast-fed, it may appear that there is an overall improvement in jaundice [9].

recommended. Ruling out other etiological possibilities, in particular, congenital infection (TORCH; Toxoplasmosis, Rubella, CMV, Herpes simplex virus) serology is indicated [44].

6.1. Antenatal Diagnosis Antenatal diagnosis of BA remains exceptional. BA types 1 and 2, which are rare, can be suspected on antenatal ultrasonography (US) scans when a cystic structure is detected in the liver hilum [40]. GB may be visualised later in pregnancy, suggesting a delay in its recanalisation process. When the GB remains undetectable after birth, the possibility that the patient has BA has to be carefully investigated [3]. Features of polysplenia syndrome may be detected by antenatal US [41] 6.2. Clinical Diagnosis The first step in diagnosis is the identification of conjugated hyperbilirubinemia in an infant with prolonged jaundice (beyond 2 weeks of age), pale stools, or dark urine. An examination of the color of a fresh stool specimen may be useful in differentiating cholestasis (clay stools) from indirect hyperbilirubinemia (bright yellow stools). The history and physical examination may guide diagnostic studies to identify specific causes of intrahepatic cholestasis [9]. Poddar et al., [42] reported that clay stool has a high sensitivity (86%) but low specificity (76%) in predicting BA. A similar finding was reported by ElGuindi et al., with 92.5% sensitivity and 55.6% specificity [43]. 6.3. Laboratory Diagnosis As time is an important factor in BA prognosis, a wide-ranging approach of investigation is

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High serum levels of GGT are commonly observed in infants with BA. It is still unclear if normal values of GGT may be found in patients with BA [45]. Alkaline phosphatase is produced by the epithelial cells of the bile ducts and serum levels are increased in cases of extra-hepatic obstruction, cholangitis and intrahepatic cholestasis. Since alkaline phosphatase is also produced in the bones, associated bone conditions may cause difficulties in the interpretation of results. In the case of high alkaline phosphatase levels and GGT above 600 U/L, BA or another obstructive duct lesion, or even alpha-1 antitrypsin deficiency would be the main diagnostic candidates. In cases of normal serum values for alkaline phosphatase with GGT below 100 U/L, a diagnosis of progressive familial intrahepatic cholestasis, or of an innate error of bile acid synthesis is possible. When the results for alkaline phosphatase and GGT are not very high, it is probable that a primary hepatocellular disease is present, such as idiopathic neonatal hepatitis [46]. GGT has been reported as discriminative tool of BA and at a cutoff value of 250.5 U/L it had a sensitivity of 86.7% and specificity of 65% [26]. Serum bile acid levels are increased after birth and remain high for the first month of life, thereafter slowly declining to normal childhood levels by 1 year of age. Serum and urinary bile acids are increased further in children with cholestatic liver disease. Furthermore, the pattern of bile acid elevations in BA is not different from that of other neonatal cholestatic liver diseases, except for progressive familial intrahepatic cholestasis [47]. The cholestasis of BA is not fully evident at birth but worsens thereafter. So, pathological elevations of serum and urinary bile acids may not be present until 2-4 weeks of age. Thus, bile acid levels cannot be used alone for the screening and early detection of BA [48]. Progressive hepatic fibrosis, in spite of successful Kasai procedure, is a major problem in patients with BA. Some serum markers have been used to assess the stage of hepatic fibrosis before and after surgery. Serum hayaluronic acid and laminin were found to be a significant markers of liver fibrosis in patients with BA [49, 50]. Furthermore, serum procollagen III peptide and type IV collagen were described to be significant prognostic markers for the outcome of BA after the corrective surgery. Lower levels of such markers were

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associated with functions [51].

better

outcome

and

good

liver

6.4. Imaging a. Plain X-Ray While X-ray may reveal situs inversus or dextrocardia associated with some cases of BA, it may also reveal different etiologies of cholestasis. Alagille syndrome may be suspected if a vertebral image showed butterfly wing. Congenital toxoplasmosis, or CMV may cause cerebral calcifications. Periostitis and osteochondritis were found to be highly indicative of syphilis [44]. b. Ultrasonography A rapid, non-invasive investigative method, and, when performed by a well-trained professional, it provides excellent results. An accurate diagnosis of BA is possible if multiple US features are carefully analyzed [52]. It is extremely useful in the diagnosis of choledochal cysts and also in ing the absence of the GB, which may suggest a diagnosis of BA. US play a role in screening patients with infantile cholestasis, mainly focusing on the size, shape and contractility of GB. Nevertheless, if changes in GB volume occur postfeeding in serial US analysis, BA cannot be ruled out. Despite difficulties in identification due to its small volume, the contractibility of the GB in BA can be observed in a percentage of cases due to a patent bile duct [53]. US evaluate congenital anomalies associated with BA. Triangular cord (TC)-sign which represents a coneshaped fibrotic mass cranial to the bifurcation of the portal vein is also a useful diagnostic criterion [54]. The presence of the TC-sign in the US examination has shown to be correct in 95% of BA diagnoses, with 85% sensitivity and 100% specificity [55]. False negative TC-sign results may occur in some BA cases due to hepatic radicles, such as hypoplasic or aplasic ducts or fibrous hepatic ducts, even at early stages [56]. However, this sign does not present or cannot be found in every patient, and it is largely dependent on operators' techniques and experience. Furthermore, it would be difficult to visualize TC-sign if the patient is very young with hepatic maldevelopment or the resolution of ultrasonic apparatus is poor [57]. A recent study reported that TC-sign has 59.3% sensitivity and 88.9% specificity in predicting BA [43]. Abnormal GB is also an important positive pointer to BA, but this is less reliable as an isolated finding in the

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absence of other US features of BA. Abnormal GB was observed in infants with cystic fibrosis. Infants with no US evidence of BA will still require further investigation to establish the cause of their conjugated hyperbilirubinemia. Tiao et al., [58] reported that, GB lengths < 1.5 cm had 77.4% sensitivity, 69.8% specificity for the diagnosis of BA. This finding is in agreement with that of El-Guindi et al., [43] who found that GB length of less than 20.5 mm is 81.4% sensitive and 70.3% specific for BA. In addition, non-contractile GB had a high sensitivity (92.5%), but low specificity (51.9%) in discriminating BA. c. Color Doppler US The presence of angiographically perivascular arterial tufts in the periphery of the hepatic arterial circulation (hepatic subcapsular flow) was reported in patients with BA and suggested that these findings might be useful in the diagnosis of BA [59]. Color Doppler US was used instead of angiography to evaluate hepatic arterial changes. On color Doppler US images, an enlarged hepatic artery and hepatic arterial flow that extended to the hepatic surface were seen in all patients with BA. It had a sensitivity and specificity of 100% and 86% respectively in predicting BA [60]. A similar study reported that hepatic subcapsular flow was found in 96.3% of BA group compared to 3.7% in non-BA group with 96.3% of both sensitivity and specificity in discriminating infants with BA from those with non-BA [43]. Hepatic artery diameter (HAD) was found to be significantly larger in patients with BA (2.1 ± 0.7 mm) than in patients with non-BA (1.5 ± 0.4 mm) (P <0.001) and control subjects (1.5 ± 0.4 mm) (P <0.001) [43]. In addition Humphrey and Stringer [52] reported that HAD was significantly larger in the BA group than in the nonBA group (2.2 ± 0.59 mm vs. 1.6 mm ± 0.4 mm, respectively; P < 0 .001). The increased size of the hepatic artery may be secondary to increased arterial resistance from hypertrophy of the media of intrahepatic arteries, which has been observed specifically in BA [43]. Kim et al., [61] reported that, the optimal cutoff value of HAD was defined as 1.5 mm which had 92% sensitivity, 87% specificity, and 89% accuracy. This enlargement may be a compensatory change to improve the blood supply for the biliary tree, a secondary change of liver cirrhosis, or an essential vascular malformation. El-Guindi et al., reported that HAD at a cutoff value of 2.05 mm had 77.8% sensitivity and 70.4% specificity in discriminating BA [43].

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d. Hepatobiliary Scintigraphy

has been reported to be inferior to that of liver biopsy [35].

These procedures are invasive and time consuming and do not significantly increase the accuracy of diagnosis [62]. Normal hepatic uptake of the radiotracer occurs within the first 10-15 minutes after injection, but the excreted tracer reaches the duodenum within 1 hour. If there is an excellent accumulation of the radiotracer in the liver but no bowel activity at 24 hours, the diagnosis of BA would be possible [57]. DISIDA Tc99m (Tc99m linked to 2.6-diisopropyl imino diacetic acid) and BRIDA Tc99m isotopes (Tc99m linked to 2.4.6-trimethyl-3-bromo imino diacetic acid), are frequently used in radioisotope scan. They have a very short half-life, low gamma ray emissions, very good concentration in the liver, non-conjugated excretion in the bile and a low renal excretion level. The BRIDA is offering the advantage that 98% of the dose istered is eliminated by the liver, while with DISIDA hepatic elimination is 85% [63]. The DISIDA Tc99m test is not recommended when conjugated bilirubin levels are over 20 mg/dl. In such cases BRIDA Tc99m should be employed, since, even with high levels of bilirubin, it maintains hepatic capture levels of 70%. Premature, very low birth weight newborns and children on total parentral nutrition, even with pervious presence of bile ducts, may not present excretion of the radiopharmaceutical to the intestine. In these cases there is indication to repeat examination two weeks later [64]. For patients in whom no intestinal tracer excretion is detected even after 24 h, scintigraphy is repeated after giving them ursodeoxycholic acid for 48–72 hrs before the second scan and is continued till the second scan is over. These additional procedures add to the time and expense of diagnosis; however, the overall specificity and accuracy in the event of a non draining scintigraphic picture remain far from being satisfactory [65]. Although hepatic scintigraphy showing definite biliary excretion excludes BA, the absence of excretion has poor predictive value because any form of severe cholestasis may show similar findings [66]. Thus nonexcretion of radioisotope neither confirms the diagnosis of BA, nor rules out the diagnosis of causes other than BA [67]. Yet, hepatobiliary scintigraphy had 80% sensitivity, 72.9% specificity, and 74.1% accuracy [68]. The diagnostic accuracy of hepatobiliary scintigraphy

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6.5. Liver Biopsy In many cases, the clinical and radiographic findings are not diagnostic and histologic findings are critical in patient management decisions [35]. Liver biopsy can correctly predict extrahepatic biliary obstruction in more than 90% of cases, directing the evaluation toward cholangiography [69, 70]. Hepatic histology does not differentiate patients with the embryonic and perinatal forms of BA [71]. Lee and Looi [72], reported that, the presence of moderate to severe bile ductular proliferation (91%) was the most consistent histological feature noted in BA with the highest sensitivity (91%) and specificity (88%) for its diagnosis. They reported bile plugs in 70% of their cases with 68% sensitivity and 86% specificity for the diagnosis of BA. Rastogi et al., [34] reported that ductular proliferation, bile plugs and portal fibrosis emerged as the best indicators of BA. Moreover, Russo et al., [73] found a great difference between BA and non-BA cases where bile duct proliferation, bile plugs in ducts and canaliculi, and the more severe grades of portal fibrosis were in favor of BA cases. El-Guindi et al., [43] reported that ductular proliferation had 100% sensitivity and 88% specificity, while bile plugs had 96.3% sensitivity and 64% specificity in diagnosing BA. 6.6. Duodenal Tube Test (DTT) A nasogastric tube is put into the distal portion of the duodenum and the liquid collected for 24 hours. If no bile fluid is seen, the test is prolonged for a further 24 hours. The enteral istration of magnesium sulfate at 25%, with a dosage of 1 ml/kg, or I.V cholecystokinin, can be performed when biliary fluids are negative 24 hours after the insertion of the duodenal tube [63]. DTT test showed a sensitivity of 97.3%, and specificity of 93.7%, a positive predictive value of 92.3% and a negative predictive value of 98.5%. DTT is not highly invasive, it is inexpensive and it may be performed by trained personnel with few specialized resources. Its high sensitivity, specificity and predictive value make it a useful tool in the differential diagnosis of infantile cholestatic jaundice, particularly in the diagnosis of BA [62]. The presence of bile excludes the possibility of BA; yet, the absence of bile does not necessarily indicate BA.

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6.7. Cholangiography a. Endoscopic Retrograde Cholangiopancreatography (ER) After the application of the radiological contrast into the papilla of Vater, it is possible to observe whether or not there is progression through the bile and pancreatic ducts [63]. ER has a sensitivity of 86 %, a specificity of 94 % in diagnosing BA [74]. b. Magnetic Resonance Cholangiopancreatography (MR) MR is a reliable non-invasive imaging technique for the diagnosis of BA and could help in early referrals from pediatricians who may spend much time seeking non-surgical causes for jaundice in infants. Preoperative MR is highly recommended to avoid unnecessary surgery in infants with cholestatic jaundice [75]. It has been reported that a small GB by MR can be considered highly suggestive of BA [76]. Periportal thickening in the MR image seems to represent periportal fibrosis on histologic examination and increased sonographic echo in the periportal area [77]. MR is more expensive than hepatobiliary scintigraphy and not available in all hospitals. One of the vulnerable points of MR is that it does not show the bile flow itself as does hepatobiliary scintigraphy or ER [75].

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GB were found laparoscopically in some infants with BA. However, in case of neonatal hepatitis, the liver was smooth, sharp-edged, and chocolate brown in color and simultaneous cholangiography showed the age of the contrast material into the proximal biliary tract and the intestinal system. Laparoscopic guided puncturing with a needle was used to wash the bile duct from the GB to decrease jaundice in patients with inspissated bile syndrome, thus unnecessary laparotomy was avoided in 25% of the patients [57]. 7. DIFFERENTIAL DIAGNOSIS A major challenge in NC is to differentiate BA from other non-atretic causes. In developing countries there are considerable problems of late referral of NC cases and performing surgery without prelaparotomy liver biopsy that contributes to a high proportion of negative laparotomy and increased morbidity [34]. Medical causes of NC must be excluded [3]. The main differential diagnosis of a biliary obstructive pattern in a liver biopsy of a cholestatic infant includes choledochal cysts, bile duct strictures, alpha-1 antitrypsin deficiency, total parentral nutritionassociated cholestasis, cystic fibrosis, progressive familial intrahepatic cholestasis type 3, North American Indian childhood cirrhosis (cirhin deficiency), Alagille syndrome [78], CMV hepatitis and inspissated bile syndrome.

c. Intra-Operative Cholangiograpy (IOC) IOC is performed when other methods do not permit a definitive diagnosis. As patients with intrahepatic cholestasis may have their condition aggravated by anesthetic products, hemodynamic alterations and infections, the investigation which precedes IOC should be as thorough as possible, in an attempt to achieve a non-invasive diagnosis. IOC should be performed at a medical center which is capable of performing the hepatoportoenterostomy immediately if necessary [44]. IOC is the gold-standard for the diagnosis of BA. However, the rate of negative laparotomy findings without preoperative liver biopsy is much higher than that with a preoperative liver biopsy (28% vs. 11%). Biopsy and IOC, both invasive procedures, become essential in such cases to confirm the diagnosis. Among the 3 commonly used tests in NC (US, hepatobiliary scintigraphy, and liver biopsy), liver biopsy is the most accurate but most invasive test [65]. 6.8. Diagnostic Laparoscopy A coarse, irregular, greenish-brown liver with some degree of fine angiomatous development and an atretic

8. MANAGEMENT 8.1. Surgical Management The current surgical management of BA patients involves two steps: Kasai operation (in the neonatal period), which aims to restore bile flow and LTx in children for whom the Kasai operation has failed in its primary aim or for whom complications of biliary cirrhosis have supervened [3]. a. Kasai Operation (Hepatoporto-Enterostomy) There is an increased need for early and correct diagnosis of BA because timely surgical portoenterostomy is necessary for improved biliary drainage. Kasai procedures appear to have the best outcome in children younger than 60 to 80 days [79]. The Kasai operation is an accepted method of achieving bile drainage in BA [80]. Reports from several institutions in Japan show that more than 80% of BA patients become jaundice-free after the Kasai operation. A favorable course depends essentially on early surgical intervention [81]. However, progressive

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liver disease develops in a few patients with successful Kasai operations and LTx is needed for patients with frequent postoperative cholangitis and for those with liver cirrhosis [82].

after surgery and a pediatric end-stage liver disease score approach [87]. In children with the syndromic variants of BA, associated anomalies, especially congenital cardiac malformations, increase the risk of both early mortality and morbidity [88].

Clinical outcomes after the Kasai operation can be divided into three categories; patients who continue in a jaundice-free state and reach adulthood with few manifestations of liver disease and portal hypertension; patients who continue in a jaundice-free state but whose quality of life is impaired because of some manifestations of liver disease owing to ongoing cirrhosis, and who thus need follow-up in planning LTx, and finally patients whose disease process continues, leading to death from cholestatic liver failure within the first two years of life unless successful LTx is achieved [80]. If the Kasai operation succeeds in restoring bile flow, the stools become colored and jaundice fades. The evolution of the biliary cirrhosis is prevented or at least delayed. Survival with the native liver has been reported up to adulthood [3]. The most common complications following the Kasai procedure include ascending cholangitis which occurs in the first weeks or months after the Kasai procedure in 30%-60% of cases [3]. Portal hypertension occurs in at least two-thirds of the children after porto-enterostomy, even in those with complete restoration of bile flow [83]. Hepatopulmonary syndrome and pulmonary hypertension may occur leading to hypoxia, cyanosis, dyspnea and digital clubbing [3]. Hepatocarcinomas, hepatoblastomas [84] and cholangiocarcinoma [85] have been described in the cirrhotic livers of patients with BA. Screening for malignancy has to be performed regularly in the followup of patients who underwent a successful Kasai operation [3]. b. Liver Transplantation Indications for LTx depend on the success of Kasai portoenterostomy and the rate of development of complications. In infants in whom bile drainage is not achieved, LTx is usually indicated within 6 months to 2 years of age. However, in those who have had a successful procedure, LTx should be considered in the presence of cirrhosis with hepatic dysfunction, or development of portal hypertension with ascites and variceal bleeding unresponsive to endoscopic management [86]. Investigation of factors that predict the need for LTx help with planning and counseling of families. Such factors are the concentration of bilirubin at 30 days

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With advances in surgical techniques and management, children with BA after LTx can achieve satisfactory survival, although there remains a high risk of complications in the early postoperative period [89]. 8.2. Adjuvant Therapy Effective postsurgical management includes prevention and treatment of complications such as cholangitis and provision of effective nutritional and family [88]. Prophylactic antibiotics (to prevent cholangitis) and choleretic agents are commonly prescribed, although definitive evidence ing their use is lacking [90]. All infants should have supplementation of nutrition and fat-soluble vitamins (A, D, E, and K) to prevent malnutrition, overcome fat malabsorption and reduce the effects of excess catabolism. In refractory cases, parenteral vitamins might be needed. Steatorrhoea from fat malabsorption can be managed by provision of between 40% and 60% of fat in the feed as medium-chain triglycerides [91]. Supplementation should contain high-energy, high-protein feed that provides between 110–160% of the recommended daily amount [88]. 9. PROGNOSIS OF BA Several prognostic factors have been identified in BA patients. Some of them are related to characteristics of the disease. The prognosis of the Kasai operation is worse when BA is associated with a polysplenia syndrome [92], when macroscopic obstructive lesions of extra-hepatic biliary remnant are diffuse (prognosis worsens from type 1 to type 3) [3], when histological obliteration of the bile ducts (especially at porta hepatis) is more severe and when liver fibrosis is more extensive at the time of the Kasai operation [93]. Other prognostic factors are related to the management of BA patients and can be improved [3]. The four year survival with native liver after Kasai operation is 43%-51% and the four year survival after LTx is 89%-90% [94]. 10. CONCLUSION In spite of the rare incidence of BA, it represents about one third of all NC. Effective treatment largely depends on early diagnosis and discrimination from

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ABBREVIATIONS

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Davenport M, Dhawan A. Epidemiologic study of infants with biliary atresia. Pediatrics 1998; 101(4 Pt 1): 729-30. http://dx.doi.org/10.1542/peds.101.4.729a

BA

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Bezerra JA, Tiao G, Ryckman FC, et al. Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet 2002; 360(9346): 1653-9. http://dx.doi.org/10.1016/S0140-6736(02)11603-5

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Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 2003; 37(1): 4-21. http://dx.doi.org/10.1097/00005176-200307000-00003

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Davenport M, Gonde C, Redkar R, et al. Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia. J Pediatr Surg 2001; 36(7): 101725. http://dx.doi.org/10.1053/jpsu.2001.24730

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HH AK, Nowicki MJ, Kuramoto KI, Baroudy B, Zeldis JB, Balistreri WF. Evaluation of the role of hepatitis C virus in biliary atresia. Pediatr Infect Dis J 1994; 13(7): 657-9. http://dx.doi.org/10.1097/00006454-199407000-00015

other causes of cholestasis. Clinical, laboratory, radiological and histopathological parameters are all helpful in diagnosis, yet, no single parameter is 100% diagnostic. So they are all helpful but not conclusive leaving IOC as the gold-standard for diagnosis. Combining different parameters may improve predictability and early diagnosis of BA and decrease the need for the invasive IOC. CONFLICT OF INTERESTS The authors declare that they have no competing interests.

= Biliary atresia

BRIDA Tc99m = Tc99m linked to 2.4.6-trimethyl-3bromo imino diacetic acid CMV

= Cytomegalovirus

DISIDA Tc99m = Tc99m linked to imino diacetic acid

2.6-diisopropyl

DPM

= Ductal plate malformation

DTT

= Duodenal tube test

ER

= Endoscopic retrograde pancreatography

GB

= Gallbladder

GGT

= Gamma glutamyl transpeptidase

HAD

= Hepatic artery diameter

Hnf6

= Hepatocyte nuclear factor 6

IOC

= Intraoperative cholangiography

MR

= Magnetic resonance cholangiopancreatography

NC

= Neonatal cholestasis

TC

= Triangular cord

US

= Ultrasonography

cholangio-

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Received on 16-04-2013

Accepted on 13-05-2013

45

Published on 25-06-2013

http://dx.doi.org/10.12970/2308-6483.2013.01.01.6

© 2013 Sira et al.; Licensee Synergy Publishers. This is an open access article licensed under the of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.