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1.  Biliary atresia 
Biliary atresia (BA) is a cholangiodestructive disease affecting biliary tract, which ultimately leads to cirrhosis, liver failure and death if not treated. The incidence is higher in Asian countries than in Europe. Up to 10% of cases have other congenital anomalies, such as polysplenia, asplenia, situs inversus, absence of inferior vena cava and pre-duodenal portal vein, for which we have coined the term Biliary Atresia Splenic Malformation (BASM) syndrome. For these infants the aetiology lies within the first trimester of gestation. For others affected with BA, aetiology is more obscure and perinatal destruction of fully-formed ducts perhaps by the action of hepatotropic viruses has been suggested. Whatever the cause, the lumen of the extrahepatic duct is obliterated at a variable level and this forms the basis for the commonest classification (Types I, II, III). All patients with BA present with varying degree of conjugated jaundice, pale non-pigmented stools and dark urine. Key diagnostic tests include ultrasonography, biochemical liver function tests, viral serology, and (in our centre) a percutaneous liver biopsy. In some centres, duodenal intubation and measurement of intralumenal bile is the norm. Currently BA is being managed in two stages. The first stage involves the Kasai operation, which essentially excises all extrahepatic biliary remnants leaving a transected portal plate, followed by biliary reconstruction using a Roux loop onto that plate as a portoenterostomy. If bile flow is not restored by Kasai procedure or life-threatening complications of cirrhosis ensue then consideration should be given to liver transplantation as a second stage. The outcome following the Kasai operation can be assessed in two ways: clearance of jaundice to normal values and the proportion who survive with their native liver. Clearance of jaundice (<2 mg/dL or <34 µmol/L) after Kasai has been reported to be around 60%, whereas five years survival with native liver ranges from 40% to 65%.
PMCID: PMC2788439  PMID: 20011467
Biliary atresia; surgical jaundice
2.  Biliary atresia 
Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence varies from 5/100,000 to 32/100,000 live births, and is highest in Asia and the Pacific region. Females are affected slightly more often than males. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. BA is not known to be a hereditary condition. No primary medical treatment is relevant for the management of BA. Once BA suspected, surgical intervention (Kasai portoenterostomy) should be performed as soon as possible as operations performed early in life is more likely to be successful. Liver transplantation may be needed later if the Kasai operation fails to restore the biliary flow or if cirrhotic complications occur. At present, approximately 90% of BA patients survive and the majority have normal quality of life.
PMCID: PMC1560371  PMID: 16872500
3.  Home intravenous antibiotic treatment for intractable cholangitis in patients with biliary atresia following Kasai portoenterostomies 
Patients with biliary atresia (BA) treated with Kasai portoenterostomy may later develop intractable cholangitis (IC) that is unresponsive to routine conservative treatment. It may cause biliary cirrhosis and eventually hepatic failure with portal hypertension. Control of IC requires prolonged hospitalization for the administration of intravenous antibiotics. To reduce the hospitalization period, we designed a home intravenous antibiotic treatment (HIVA) which can be administered after initial inpatient treatment. In this study, we reviewed the effects of this treatment.
We reviewed medical records of 10 patients treated with HIVA for IC after successful Kasai portoenterostomies performed for BA between July 1997 and June 2009.
The duration of HIVA ranged from 8 to 39 months (median, 13.5 months). The median length of hospital stay was 5.7 days per month for conventional treatments to manage IC before HIVA and, 1.5 days per month (P = 0.012) after HIVA. The median amount of medical expenses per month was reduced by about one tenth with HIVA. One patient underwent liver transplantation due to uncontrolled esophageal variceal bleeding, but the other nine patients had acceptable hepatic function with native livers.
HIVA may be an effective primary treatment for IC after Kasai portoenterostomies for BA, and reduce length of hospital stay and medical expense.
PMCID: PMC3204694  PMID: 22066060
Biliary atresia; Intractable cholangitis; Home intravenous antibiotics treatment
4.  Extrahepatic biliary atresia: Correlation of histopathology and liver function tests with surgical outcomes 
To correlate the age at surgery, liver function tests, and hepatic and portal tract histo-pathological changes with surgical outcome in the form of disappearance of jaundice in extrahepatic biliary atresia (EHBA).
Materials and Methods:
This is a retrospective study of 39 cases of EHBA. There were 19 males and 10 females. Kasai's portoenterostomy (KPE) along with liver biopsy was performed in these patients; for purpose of correlation this biopsy was considered to be the preoperative biopsy. These patients were divided into three groups based upon surgical outcome: (A) disappearance of jaundice; (B) initial disappearance of jaundice with recurrence after 3 months; and (C) persistence of jaundice. Postoperatively, liver function tests and liver biopsies were repeated at 3 months after the KPE.
There were 11 patients in group A (28%), 21 patients in group B (54%), and seven patients in group C (18%). The age at surgery was comparable in all the three groups. The postoperative levels of serum bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGTP) showed statistically significant improvement as compared with the preoperative levels in group A and B patients. Patients belonging to group C showed no improvement in the liver functions following surgery. The preoperative hepatic histopathological changes (hepatocellular alteration, cholestasis, bile ductular proliferation, and bile duct inflammation) showed a significant difference among the three groups; patients with lesser degrees of pre-existing histopathological changes had better outcome following surgery. Fibrosis was seen in all the three groups preoperatively but the difference was not statistically significant. Group C had significant fibrosis in more than 50% patients. Additional findings, viz. ductal plate malformation (9 patients, 23%) and giant cell transformation (19 patients, 49%) did not show any correlation with surgical outcomes.
The liver function tests and the histopathological features appeared to affect the final surgical outcome of these patients. Higher degree of cholestasis, hepatocellular alteration, bile ductule proliferation, bile duct inflammation showed definite correlation with poor surgical outcome. High grade hepatic fibrosis and portal edema showed a trend towards poor outcome but did not achieve statistical significance.
PMCID: PMC3518991  PMID: 23243365
Extrahepatic biliary atresia; Kasai's portoenterostomy; liver function tests; liver histopathology; results of surgery
5.  Late complications and current status of long-term survivals over 10 years after Kasai portoenterostomy 
Whereas the Kasai portoenterostomy (KPE) is an accepted first line of surgery for bile drainage in infants with biliary atresia, its long-term effectiveness is not clear because its etiology and pathogenesis remains unknown. This study was aimed to investigate the late complications occurring in long-term survivors and the current status of living patients who survived over 10 years after KPE.
A retrospective analysis of the medical records of 32 patients who underwent KPE from 1990 to 2000 was done. We analyzed 10-year survival rates with the Kaplan-Meier method and the current status of the long-term survivors.
The overall 10-year survival rate by Kaplan-Meier method after KPE was 76.2%. Eight (25%) patients had died, including 4 who were transplanted. Nineteen (59.4%) patients survived over 10 years. Among them, 6 (31.6%) patients had portal hypertension, and 5 (26.3%) had episodes of cholangitis. Two had intrahepatic cyst and 2 had intestinal obstruction. Six (31.6%) patients have been well without any complications.
The long-term survival rate of biliary atresia is slightly improving. However, two thirds of patients suffer from various complications. One-third of survivors go on without any complication. As biliary atresia is known as a progressive inflammatory disease, careful life-long follow- up is needed in long-term survivals after KPE.
PMCID: PMC3219853  PMID: 22111083
Biliary atresia; Hepatic portoenterostomy; Survivors; Portal hypertension; Cholangitis
6.  Screening and Outcomes in Biliary Atresia: Summary of a National Institutes of Health Workshop 
Hepatology (Baltimore, Md.)  2007;46(2):566-581.
Biliary atresia is the most common cause of end-stage liver disease in the infant and is the leading pediatric indication for liver transplantation in the United States. Earlier diagnosis (<30-45 days of life) is associated with improved outcomes following the Kasai portoenterostomy and longer survival with the native liver. However, establishing this diagnosis is problematic because of its rarity, the much more common indirect hyperbilirubinemia that occurs in the newborn period, and the schedule for routine infant health care visits in the United States. The pathogenesis of biliary atresia appears to involve immune-mediated fibro-obliteration of the extrahepatic and intrahepatic biliary tree in most patients and defective morphogenesis of the biliary system in the remainder. The determinants of the outcome of portoenterostomy include the age at surgery, the center's experience, the presence of associated congenital anomalies, and the postoperative occurrence of cholangitis. A number of screening strategies in infants have been studied. The most promising are early measurements of serum conjugated bilirubin and a stool color card given to new parents that alerts them and their primary care provider to acholic stools. This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006, in Bethesda, MD, that addressed the issues of outcomes, screening, and pathogenesis of biliary atresia.
PMCID: PMC3888317  PMID: 17661405
7.  Biliary Atresia: 50 Years after the First Kasai 
ISRN Surgery  2012;2012:132089.
Biliary atresia is a rare neonatal disease of unknown etiology, where obstruction of the biliary tree causes severe cholestasis, leading to biliary cirrhosis and death in the first years of life, if the condition is left untreated. Biliary atresia is the most frequent surgical cause of cholestatic jaundice in neonates and should be evoked whenever this clinical sign is associated with pale stools and hepatomegaly. The treatment of biliary atresia is surgical and currently recommended as a sequence of, eventually, two interventions. During the first months of life a hepatoportoenterostomy (a “Kasai,” modifications of which are discussed in this paper) should be performed, in order to restore the biliary flow to the intestine and lessen further damage to the liver. If this fails and/or the disease progresses towards biliary cirrhosis and life-threatening complications, then liver transplantation is indicated, for which biliary atresia represents the most frequent pediatric indication. Of importance, the earlier the Kasai is performed, the later a liver transplantation is usually needed. This warrants a great degree of awareness of biliary atresia, and the implementation of systematic screening for this life-threatening pathology.
PMCID: PMC3523408  PMID: 23304557
8.  Diversity of Disorders Causing Neonatal Cholestasis – The Experience of a Tertiary Pediatric Center in Germany 
Background and Objective: Rapidly establishing the cause of neonatal cholestasis is an urgent matter. The aim of this study was to report on the prevalence and mortality of the diverse disorders causing neonatal cholestasis in an academic center in Germany.
Methods: Clinical chemistry and cause of disease were retrospectively analyzed in 82 infants (male n = 42, 51%) that had presented with neonatal cholestasis to a tertiary medical center from January 2009 to April 2013.
Results: Altogether, 19 disorders causing neonatal cholestasis were identified. Biliary atresia was the most common diagnosis (41%), followed by idiopathic cases (13%), progressive familial intrahepatic cholestasis (PFIC, 10%), cholestasis in preterm infants (10%), α1AT deficiency, Alagille syndrome, portocaval shunts, mitochondriopathy, biliary sludge (all 2%), and others. Infants with biliary atresia were diagnosed with a mean age of 62 days, they underwent Kasai portoenterostomy ~66 days after birth. The majority of these children (~70%) received surgery within 10 weeks of age and 27% before 60 days. The 2-year survival with their native liver after Kasai procedure was 12%. The time span between Kasai surgery and liver transplantation was 176 ± 73 days. Six children (7%), of whom three patients had a syndromic and one a non-syndromic biliary atresia, died prior to liver transplantation. The pre- and post-transplant mortality rate for children with biliary atresia was ~12 and ~17%, respectively.
Conclusion: Neonatal cholestasis is a severe threat associated with a high risk of complications in infancy and it therefore requires urgent investigation in order to initiate life saving therapy. Although in the last 20 years new causes such as the PFICs have been identified and newer diagnostic tools have been introduced into the clinical routine biliary atresia still represents the major cause.
PMCID: PMC4066316  PMID: 25003101
neonatal cholestasis; neonatal jaundice; biliary atresia; Kasai procedure; ERCP
9.  Dexamethasone Alters the Hepatic Inflammatory Cellular Profile Without Changes in Matrix Degradation During Liver Repair Following Biliary Decompression 
The Journal of surgical research  2009;156(2):231-239.
Biliary atresia is characterized by extrahepatic bile duct obliteration along with persistent intrahepatic portal inflammation. Steroids are standard in the treatment of cholangitis following the Kasai portoenterostomy and were liberally adopted advocated for continued suppression of the ongoing immunological attack against intrahepatic ducts. Recent reports however have failed to demonstrate an improved patient outcome or difference in the need for liver transplant in postoperative patients treated with a variety of steroid regimes compared to historical controls. In the wake of progressive liver disease despite biliary decompression steroids are hypothesized to suppress inflammation and promote bile flow without any supporting data regarding their effect on the emerging cellular and molecular mechanisms of liver repair. We have previously shown in a reversible model of cholestatic injury that repair is mediated by macrophages, neutrophils and specific matrix metalloproteinase activity (MMP8); we questioned whether steroids would alter these intrinsic mechanisms.
Rats underwent biliary ductal suspension for 7 days followed by decompression. Rats were treated with IV dexamethasone or saline at the time of decompression. Liver tissue obtained at the time of decompression or after 2 days (D2) of repair was processed for morphometric analysis, immunohistochemistry, and quantitative RT-PCR.
There was a dramatic effect of dexamethasone on the inflammatory component with the initiation of repair. Immunohistochemistry revealed a reduction of both ED1+ hepatic macrophages and ED2+ Kupffer cells in repair when compared to saline controls. Dexamethasone treatment also reduced infiltrating neutrophils by D2. TNF-α expression, increased during injury in both saline and dexamethasone groups, was markedly reduced by dexamethasone during repair (D2) whereas IL-6, IL-10 and CINC-1 remained unchanged when compared to saline controls. Dexamethasone reduced both MMP8 and TIMP1 expression by D2, whereas MMP9, 13, and 14 were unchanged when compared to sham controls. Despite substantial cellular and molecular changes during repair, collagen resorption was the same in both groups
Dexamethasone has clear effects on both the hepatic macrophage populations and infiltrating neutrophils following biliary decompression. Altered MMP and TIMP gene expression might suggest that steroids have the potential to modify matrix metabolism during repair. Nevertheless, successful resorption of collagen fibrosis proceeded presumably through other MMP activating mechanisms. We conclude that steroids do not impede the rapid intrinsic repair mechanisms of matrix degradation required for successful repair.
PMCID: PMC2749887  PMID: 19592011
10.  The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival 
Annals of surgery  2011;254(4):577-585.
The goals of this study were to describe the clinical and anatomic features of infants undergoing Kasai portoenterostomy (KPE) for biliary atresia (BA), and to examine associations between these parameters and outcomes.
Infants enrolled in the prospective Childhood Liver Disease Research and Education Network, who underwent KPE were studied. Patients enrolled in a blinded, interventional trial were excluded from survival analysis. Primary end-points were successful surgical drainage (total bilirubin less than 2 mg/dL within the first three months), transplant-free survival (Kaplan-Meier), and time to transplant/death (Cox regression).
KPE was performed in 244 infants (54% female; mean age 65± 29 days). Transplant-free survival was 53.7% and 46.7% at 1 and 2 years post-KPE. The risk of transplant/death was significantly lower in the 45.6% of patients who achieved successful bile drainage within 3 months post-KPE (HR 0.08, p<0.001). The risk of transplant/death was increased in patients with porta hepatis atresia (Ohi Type II and III vs. Type I; HR 2.03, p=0.030), non-patent common bile duct (Ohi Subtype b, c, and d vs. a; HR 4.31, p=0.022), BA splenic malformation syndrome (HR 1.92, p=0.025), ascites > 20 ml (HR=1.90, p=0.0230), nodular liver appearance compared to firm (HR=1.61, p=0.008), and age at KPE ≥ 75 days (HR 1.73, p<0.002). Outcome was not associated with gestational age, gender, race, ethnicity, or extent of porta hepatis dissection.
Anatomic pattern of BA, BASM, presence of ascites and nodular liver appearance at KPE, and early postoperative jaundice clearance are significant predictors of transplant-free survival.
PMCID: PMC3460800  PMID: 21869674
Biliary atresia; Kasai portoenterostomy; jaundice; hepatobiliary; Biliary Atresia Research Consortium
11.  Hepatic expression of multidrug resistance protein 2 in biliary atresia 
Biliary atresia (BA) is an idiopathic inflammatory obliterative cholangiopathy of neonates, leading to progressive biliary cirrhosis. Hepatoportoenterostomy (Kasai procedure) can cure jaundice in 30% to 80% of patients. Postoperative clearance of jaundice is one of the most important factors influencing long-term outcomes of BA patients. Multidrug resistance protein 2 (MRP2) is one of the canalicular export pumps located in hepatocytes; it exports organic anions and their conjugates (e.g., bilirubin) into bile canaliculus. Although MRP2 is an essential transporter for the excretion of bilirubin, its role in the clinical course of BA patients is unclear. The present study investigated the relationship between hepatic MRP2 expression and clinical course in BA patients, with particular emphasis in curing jaundice after hepatoportoenterostomy.
No significant differences in hepatic MRP2 expression level were observed between BA and controls groups. There was no correlation between MRP2 expression and age at time of surgery in BA and control groups. In BA patients, MRP2 expression level in the jaundice and jaundice-free group did not differ significantly (2.0 × 10-4 vs 3.1 × 10-4, p = 0.094). Although the serum level of total bilirubin just before surgery did not correlate with MRP2 expression level (rs = 0.031, p = 0.914), the serum level of total bilirubin measured at 2 weeks (rs = -0.569, p = 0.034) and 4 weeks after surgery (rs = -0.620, p = 0.018) were significantly correlated with MRP2 expression level. Furthermore, MRP2 expression level was inversely correlated with ratio of change in serum total bilirubin level over 4 weeks (rs = -0.676, p = 0.008), which represents the serum bilirubin level measured at 4 weeks after surgery divided by value just before surgery. There was no correlation between expression level of MRP2 and nuclear receptors, such as retinoid × receptor α, farnesoid × receptor, pregnane × receptor, or constitutive androstane receptor.
Hepatic MRP2 expression level was associated with postoperative clearance of jaundice in BA patients, at least within 1 month after hepatoportoenterostomy. This finding suggests that not only morphological appearance of the liver tissue but also the biological status of hepatocytes is important for BA pathophysiology.
PMCID: PMC3161838  PMID: 21813008
12.  Results of surgery in 88 consecutive cases of extrahepatic biliary atresia. 
Of 88 cases of extrahepatic biliary atresia, satisfactory bile flow has been established in 46% of the patients who have undergone portoenterostomies and in 25% of patients with hepaticojejunostomies. Histological analysis of the extrahepatic biliary tissue has not shown a consistent correlation with outcome of operation, except that the patients with one or two large residual ducts lined with columnar epithelium have a better chance of developing bile flow. Cholangitis developed in 43% of the cases, and co-trimoxazole was not shown to have any beneficial effect in a small prospective trial in 18 patients. Severe haemorrhage from oesophageal varices has occurred in 4 jaundice-free survivors. Seventeen patients are now over 3 years of age and thriving but many show persistent elevation of liver enzymes.
PMCID: PMC1437961  PMID: 7086788
13.  Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant 
Gut  2001;49(2):276-281.
The clinical and pathological findings of four females with primary biliary cirrhosis (PBC) with an unusual and hitherto not well recognised course are reported. Patients suffered severe pruritus and weight loss with progressive icteric cholestasis which did not respond to such treatments as ursodeoxycholic acid and immunosuppressives. In all cases liver histology revealed marked bile duct loss without however significant fibrosis or cirrhosis. Further diagnostic studies and repeat biopsies confirmed the absence of liver cirrhosis as well as other potential causes of hyperbilirubinaemia. Comparison of the fibrosis-ductopenia relationship for our cases with that for a group of 101 non-cirrhotic PBC patients indicated that in the former the severity of bile duct loss relative to the amount of fibrosis was significantly higher. The proportion of portal triads containing an interlobular bile duct was 3%, 4%, 6%, and 10% compared with 45% (median; range 8.3-100%) for controls (p<0.001). Three patients received a liver transplant 6-7 years after the first manifestation of PBC because of progressive cholestasis, refractory pruritus, and weight loss, while the fourth patient is considering this option. In one case cirrhosis had developed at the time of transplantation while the others still had non-cirrhotic disease. These cases suggest that cholestatic jaundice in non-cirrhotic PBC may be secondary to extensive "premature" or accelerated intrahepatic bile duct loss. Although the extent of fibrosis may be limited initially, progression to cirrhosis appears to be inevitable in the long run. Despite intact protein synthesis and absence of cirrhotic complications, liver transplantation in the pre-cirrhotic stage for preventing malnutrition and to improve quality of life should be considered for these patients.

Keywords: primary biliary cirrhosis; jaundice; ductopenia; portal tract; cholestasis; liver biopsy
PMCID: PMC1728410  PMID: 11454806
14.  The multiple facets of ABCB4 (MDR3) deficiency 
Opinion Statement
ABCB4 (MDR3) is a lipid translocator that moves phosphatidylcholine from the inner to outer leaflet of the canalicular membrane for extraction into the lumen by bile salts. Genetic mutations of ABCB4 lead to 3 distinct but related hepatobiliary diseases. Progressive familial intrahepatic cholestasis (PFIC) type 3 is a chronic cholestatic syndrome characterized by a markedly elevated GGTP. Patients present later in life than other types of PFIC with jaundice, pruritis and hepatosplenomegaly. Peri-portal inflammation progresses to biliary cirrhosis and eventually causes portal hypertension. Ursodeoxycholic acid (UDCA), which alters biliary bile composition, normalizes liver function tests in approximately half of treated PFIC type 3 patients. Partial or non-responders will eventually require liver transplantation. Gallstone patients with ABCB4 mutations may have Low Phospholipid Associated Cholelithiasis Syndrome. This is characterized by cholesterol gallstones and intrahepatic microlithiasis, along with recurrent biliary symptoms, despite cholecystectomy. A distinct group of patients with ABCB4 mutations may also develop intrahepatic brown pigment stones. The current treatment for these two diseases is UDCA, which may improve biliary symptoms even before the dissolution of stones occurs. Additional therapies such as Farnesoid X receptor ligands/agonists and benzfibrates show promise as future therapeutic modalities. Intrahepatic cholestasis of pregnancy affects pregnant women with abnormal ABCB4 variants. These women suffer from disabling pruritis and may experience steatorrhea as well. Their fetuses are at high risk for prematurity and still births. The definitive treatment for this condition is delivery of the baby. In the interim, limited fat intake, fat soluble vitamin supplementation and UDCA, with or without S-adenosylmethionine can provide symptomatic relief. In the future, additional hepatobiliary diseases related to ABCB4 mutations are likely to be identified. It is likely that this will result in the discovery of additional therapies for PFIC Type 3, gallstones and intrahepatic cholestasis of pregnancy.
PMCID: PMC3888315  PMID: 18221610
15.  Anaesthesia for biliary atresia and hepatectomy in paediatrics 
Indian Journal of Anaesthesia  2012;56(5):479-484.
The scope of this article precludes an ‘in depth’ description of all liver problems and I will limit this review to anaesthesia for biliary atresia — a common hepatic problem in the very young — and partial hepatectomy in older children. I will not be discussing the problems of anaesthetising children with hepatitis, cirrhosis, congenital storage diseases or liver failure. Extrahepatic biliary obstruction is an obliterative cholangiopathy of infancy which is fatal if untreated. Diagnosis involves exclusion of other causes of neonatal jaundice and treatment involves a hepatico portoenterostomy carried out at the earliest. This is a review of current concepts in anaesthesia and postoperative management of neonates with extrahepatic biliary atresia. Anaesthesia for hepatic resection has seen great changes in recent times with the improvement in surgical techniques, technology and a better understanding of the underlying physiology. These are reviewed along with the problems of postoperative pain management.
PMCID: PMC3531003  PMID: 23293387
Anaesthesia; biliary atresia; hepatectomy; paediatrics; pain relief
16.  Prognosis of extrahepatic biliary atresia. 
Archives of Disease in Childhood  1989;64(2):214-218.
We carried out a retrospective investigation of the 89 patients with extrahepatic biliary atresia born in The Netherlands during a 10 year period. Of these 89 patients 10 had a diagnostic laparotomy only. Eight patients had an anastomosis between the proximal bile duct and the intestine, and the remaining 71 had hepatic portoenterostomies. Bile drainage was re-established in 46 (65%). After successful hepatic portoenterostomy the development of cholangitis was the most important determinant of long term survival; five year survival was 54% in the 19 patients who had cholangitis and 91% in the 27 who did not. In the whole group of 71 patients the five year survival was 47%. Seventeen patients were at least 5 years of age at the time of writing, three of whom had had liver transplantation. Three patients have cirrhosis and hyperbilirubinaemia, and the other 11 have normal bilirubin concentrations and normal or slightly raised transaminase activities. To improve these results early surgical intervention in all children with extrahepatic biliary atresia is necessary, as are better methods of prophylaxis and treatment of cholangitis.
PMCID: PMC1791862  PMID: 2930227
17.  Extrahepatic biliary atresia with choledochal cyst: Prenatal MRI predicted and post natally confirmed: A case report 
Extrahepatic biliary atresia (EHBA) is an uncommon cause of neonatal jaundice. Antenatal Magnetic Resonance Imaging (MRI) diagnosis of EHBA has not been published to the best of our knowledge till date. EHBA with cystic component is likely to be mistaken for choledochal cyst. A case that was antenatally predicted and postnatally confirmed by surgery and histopathology is being reported. All imaging signs are analyzed herewith. Imaging helps in the prediction of EHBA and also helps in early postnatal surgical referral which in turn improves the results of Kasai's portoenterostomy.
PMCID: PMC3843332  PMID: 24347854
Choledochal cyst; extrahepatic biliary atresia; ghost triad; prominent hepatic artery; prenatal MRI; USG
18.  Neonatal jaundice: the surgical viewpoint. 
Canadian Medical Association Journal  1980;123(12):1218-1224.
There is good evidence that neonatal hepatitis, biliary hypoplasia, biliary atresia and choledochal cyst are different stages of one disease process for which the term infantile obstructive cholangiopathy has been suggested. Thanks to the work of Kasai and the operation of hepatic portoenterostomy the surgical outlook has greatly improved, although in North America it still leaves much to be desired. One cannot procrastinate too long in the hope that the patient's condition will improve spontaneously, because the surgical results are much better when the operation is performed before the patient is 10 weeks old. This article outlines the steps that should be followed in investigating neonatal jaundice, the nonsurgical measures that can be taken in an attempt to reverse or alleviate the underlying condition, and the specific role of the pediatric surgeon in the management of choledochal cyst and biliary atresia.
PMCID: PMC1705054  PMID: 7006774
19.  Staging of biliary atresia at diagnosis by molecular profiling of the liver 
Genome Medicine  2010;2(5):33.
Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis.
We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years.
Fourteen of 47 livers displayed predominant histological features of inflammation (N = 9) or fibrosis (N = 5), with the remainder showing similar levels of both simultaneously. By differential profiling of gene expression, the 14 livers had a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival.
Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes.
PMCID: PMC2887077  PMID: 20465800
20.  Role of Kasai procedure in surgery of hilar bile duct strictures 
AIM: To assess the application of the Kasai procedure in the surgical management of hilar bile duct strictures.
METHODS: Ten consecutive patients between 2005 and 2011 with hilar bile duct strictures who underwent the Kasai procedure were retrospectively analyzed. Kasai portoenterostomy with the placement of biliary stents was performed in all patients. Clinical characteristics, postoperative complications, and long-term outcomes were analyzed. All patients were followed up for 2-60 mo postoperatively.
RESULTS: Patients were classified according to the Bismuth classification of biliary strictures. There were two Bismuth III and eight Bismuth IV lesions. Six lesions were benign and four were malignant. Of the benign lesions, three were due to post-cholecystectomy injury, one to trauma, one to inflammation, and one to inflammatory pseudotumor. Of the malignant lesions, four were due to hilar cholangiocarcinoma. All patients underwent Kasai portoenterostomy with the placement of biliary stents. There were no perioperative deaths. One patient experienced anastomotic leak and was managed conservatively. No other complications occurred perioperatively. During the follow-up period, all patients reported a good quality of life.
CONCLUSION: The Kasai procedure combined with biliary stents may be appropriate for patients with hilar biliary stricture that cannot be managed by standard surgical methods.
PMCID: PMC3208369  PMID: 22072856
Kasai procedure; Hilar bile duct; Stricture; Surgery
21.  Elevated Bile Acids in Newborns with Biliary Atresia (BA) 
PLoS ONE  2012;7(11):e49270.
Biliary Atresia (BA), a result from inflammatory destruction of the intrahepatic and extrahepatic bile ducts, is a severe hepatobiliary disorder unique to infancy. Early diagnosis and Kasai operation greatly improve the outcome of BA patients, which encourages the development of early screening methods. Using HPLC coupled tandem mass spectrometry, we detected primary bile acids content in dried blood spots obtained from 8 BA infants, 17 neonatal jaundice and 292 comparison infants at 3–4 days of life. Taurocholate (TC) was significantly elevated in biliary atresia infants (0.98±0.62 µmol/L) compared to neonatal jaundice (0.47±0.30 µmol/L) and comparison infants (0.43±0.40 µmol/L), with p = 0.0231 and p = 0.0016 respectively. The area under receiver operating characteristic (ROC) curve for TC to discriminate BA and comparison infants was 0.82 (95% confidence interval: 0.72–0.92). A cutoff of 0.63 µmol/L produced a sensitivity of 79.1% and specificity of 62.5%. The concentrations of total bile acids were also raised significantly in BA compared to comparison infants (6.62±3.89 µmol/L vs 3.81±3.06 µmol/L, p = 0.0162), with the area under ROC curve of 0.75 (95% confidence interval: 0.61–0.89). No significant difference was found between the bile acids of neonatal jaundice and that of comparison infants. The early increase of bile acids indicates the presentation of BA in the immediate newborn period and the possibility of TC as newborn screening marker.
PMCID: PMC3498146  PMID: 23166626
22.  Does adjuvant steroid therapy post-Kasai portoenterostomy improve the outcome of biliary atresia? A systematic review and meta-analysis 
The role of adjuvant steroid therapy in the postoperative management of patients with biliary atresia (BA) is unclear.
To systematically review the literature and perform a meta-analysis to determine the efficacy of adjuvant steroid therapy post-Kasai portoenterostomy (KP) on BA outcome.
A systematic review and meta-analysis of randomized trials and/or observational studies that examined the role of steroids on BA outcomes published between January 1969 and June 2010 was conducted. Studies were identified using the Medline, PubMed, EMBASE and Cochrane databases.
Sixteen observational studies and one randomized controlled trial (RCT) were found. Four of the 16 observational studies (160 participants) and the RCT (73 participants) met the entry criteria and were eligible to be included in the analysis. There was no statistically significant difference in the effect of steroids either on normalizing serum bilirubin levels at six months (pooled OR 1.48 [95% CI 0.67 to 3.28]) or in delaying the need for early liver transplantation (within the first year post-KP (pooled OR 0.59 [95% CI 0.21 to 1.72]).
The present meta-analysis did not find a significant effect of steroid over standard therapy, either in normalizing serum bilirubin levels at six months or at delaying the need for early liver transplantation post-KP. RCT studies of sufficient size and comprehensive design using high-dose steroids are needed to determine the effectiveness of steroids on the short and intermediate post-KP outcomes for BA patients.
PMCID: PMC3186729  PMID: 21912769
Biliary atresia; Corticosteroids; Kasai portoenterostomy; Liver transplantation; Systematic review
23.  Liver Transplantation for Biliary Atresia 
World journal of surgery  1984;8(1):51-56.
Orthotopic liver transplantation was performed 15 months to 20 years ago in 126 recipients, all of whom were under 18 years of age. Eighty-six of these pediatric recipients were treated before 1980 with azathioprine (or cyclophosphamide) and prednisone, to which antilymphocyte globulin (ALG) usually was added. One-year patient survival was 40%. In the last 40 cases, the new drug cyclosporine has been given with low doses of steroids. The one-year patient survival increased to 65%. Both in the pre-cyclosporine era and more recently, the survival of patients with biliary atresia has been lower than in the next largest category of patients, namely, those with liver-based inborn metabolic errors. The difficulty of operation in patients with biliary atresia has been greater than in recipients with other diagnoses, partly because of previous operations such as portoenterostomy (Kasai procedure). Hepatic portoenterostomy, worthwhile as it is, has posed technical difficulties for eventual liver transplantation, particularly when complicated Roux limb techniques or venting procedures have been applied. In our total experience the longest survival after liver replacement in a child whose original diagnosis was biliary atresia is 13⅔ years.
PMCID: PMC2978657  PMID: 6367233
24.  Hepatic osteodystrophy complicated with bone fracture in early infants with biliary atresia 
World Journal of Hepatology  2012;4(10):284-287.
Biliary atresia (BA) is one of the major hepatobiliary abnormalities in infants and one of the causes of hepatic osteodystrophy. Bone disease may be caused by the malabsorption of calcium and magnesium by vitamin D in hepatobiliary diseases in which bile flow into the intestines is deficient or absent. Bone fracture before Kasai hepatic portoenterostomy or within one month after the procedure in an infant with BA is very rare. We herein report two infants: one infant with BA who initially presented with a bone fracture before Kasai hepatic portoenterostomy, and the other at 4 wk after Kasai hepatic portoenterostomy, and also provide a review of the literature. Moreover, we conclude that clinicians should consider BA in infants with bone fracture during early infancy.
PMCID: PMC3537162  PMID: 23293713
Biliary atresia; Bone fractur; Hepatic osteodystrophy; Kasai hepatic portoenterostomy; Vitamin D deficiency
25.  Hepatic function following portoenterostomy for extrahepatic biliary atresia. 
Liver structure and function in 10 patients with extrahepatic biliary atresia were studied after portoenteric anastomosis (Kasai operation). Bile flow adequate to reduce the serum bilirubin concentration was established in five patients (improved group), three of whom became anicteric. The serum bilirubin concentration did not decrease in the remaining five patients (unimproved group). Hepatic effluent collected postoperatively from both groups contained small amounts of cholesterol and bilirubin; bile salts, however, were present in the hepatic effluent of only the improved patients. Liver biopsy specimens obtained postoperatively from the five improved patients showed partial (in two) or complete (in three) relief of cholestasis; hepatic fibrosis, however, was unchanged (in one) or worse (in four). The serum concentrations of bile salts were markedly elevated, despite normal excretion of sodium sulfobromophthalein and rose bengal, in two anicteric patients studied 14 and 24 months postoperatively. It is concluded that neither structure nor function of the liver is normalized by portoenterostomy even in clinically well, anicteric patients.
PMCID: PMC1817926  PMID: 630484

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