Biliary Atresia Flashcards
Which one of the following statements concerning biliary atresia is true?
A. Without treatment, the average survival is 5 years.
B. The hallmark pathologic findings are giant cell transformation and hepatocellular necrosis.
C. There is a higher incidence in Europe and North America.
D. Ultrasound of the liver and gallbladder is an integral part of the diagnostic workup.
E. Biliary atresia is the third most common indication for pediatric liver transplantation.
ANSWER: D
COMMENTS: Biliary atresia is characterized by progressive, irreversible fibrosis of the extrahepatic and intrahepatic bile ducts.
There is no proved effective medical therapy. If surgical correction is not performed, the obliterative process progresses.
Biliary cirrhosis and portal hypertension develop, followed by death by 2 years of age.
Severe cholestasis, bile duct proliferation, and inflammatory cell infiltration are pathologic findings in biliary atresia.
Hepatocellular necrosis and giant cell transformation are seen with neonatal hepatitis.
Biliary atresia is the number one indication for pediatric liver transplantation.
Biliary atresia should be suspected in an infant with persistent neonatal jaundice and elevated conjugated bilirubin.
It occurs in 1/10,000 live births and is most prevalent in Asia.
The workup for suspected biliary atresia includes ultrasound imaging of the liver and gallbladder, hepatobiliary iminodiacetic acid (HIDA) scanning, and percutaneous liver biopsy.
Typically, the extrahepatic bile ducts cannot be seen on ultrasound imaging, and the gallbladder is diminutive or absent.
However, even with these tests, the final diagnosis often is made at surgical exploration.
An intraoperative cholangiogram will demonstrate a lack of opacification of the intrahepatic biliary tree.
When identified, a Kasai procedure is indicated. The goals of the Kasai procedure are to restore biliary flow by performing a Roux-en-Y portojejunostomy after the resection of the gallbladder, extrahepatic bile ducts, and the fibrotic portal plate.
With regard to the Kasai procedure for the treatment of biliary atresia, which of the following statements is true?
A. It is most successfully performed after 3 months of age.
B. Cholangitis rarely complicates a successful procedure.
C. Portal hypertension remains problematic despite a successful operation.
D. If hepatic transplantation is needed, an initial Kasai enterostomy is not indicated.
E. Cholangitis is an infrequent late complication.
ANSWER: C
COMMENTS: Biliary atresia occurs as a part of a spectrum of anomalies of infantile obstructive cholangiopathy.
Variable patterns of ductal involvement of the intrahepatic and extrahepatic biliary tree are seen, with 10% of patients initially having an extrahepatic disease only.
The goals of treatment are to establish biliary flow and prevent the late complications of biliary cirrhosis and hepatic failure.
Hepatoportoenterostomy, the Kasai procedure, is most successful in establishing biliary drainage when performed during the patient’s first 2 months of life.
The success rate falls dramatically after 3 months of age.
Cholangitis, biliary cirrhosis, hepatic failure, and portal hypertension remain late problems despite the fact that bile drainage is achieved.
Attempts to reduce later cholangitic complications include prolonged use of antibiotics and steroids to minimize inflammation and infection.
One- third of patients undergoing a Kasai procedure for biliary atresia will have a successful biliary drainage and require no further intervention.
One-third will initially have adequate drainage but will eventually progress to hepatic fibrosis and require transplantation.
The final third will never have adequate drainage and will require liver transplantation to survive.
Hepatic transplantation has been successful in the treatment of this problem but has not replaced biliary-enteric anastomosis as the initial procedure.
An unsuccessful hepatoportoenterostomy does not preclude later hepatic transplantation and is therefore the initial surgical management of biliary atresia.
Discuss biliary atresia.
Biliary Atresia (BA) is the most common surgical cause of conjugated jaundice in infancy, and consists of a progressive inflammatory destruction and obliteration of variable lengths of the biliary tract.
If left untreated it leads to liver failure and death within few months.
It is best treated by an attempt at restora- tion of bile flow from the native liver by excision of the extrahepatic bile ducts and reconstruction using a jejunal Roux loop (Kasai portoenterostomy).
With this clearance of jaundice of 50–60% can be achieved in large centres with appropriate adjuvant therapy.
Failure to clear jaundice or onset of complications such as recurrent cholangitis, ascites and recurrent bleeding from variceal formation are indications for liver transplantation.
What is biliary atresia?
Biliary atresia (BA) is unique to the neonatal period and first described by the Scottish paediatrician John Thomson in 1892.
It is the most common surgical cause of conjugated jaundice in infancy, and consists of a progressive inflammatory destruction and obliteration of variable lengths of the biliary tract.
If left untreated it leads to liver failure and death within few months.
A comprehensive aetiology for BA has not been exhaustively formulated yet.
Nevertheless, it is clear that the pathogenesis of the disease includes both a mechanical obliteration and in some a destructive inflammatory process of the bile ducts.
What is the incidence of BA?
It varies across the globe with relatively high incidence in Taiwan, mainland China and Japan of 1 in 5–10,000 live births to 1 in 15–20,000 in North America and Europe.
What classifications are in use for BA?
Phenotypic classification
This classification is based on objective features and represents a useful tool for the clinical assessment and management of the patients. It is possible to recognise four main groups.
- Syndromic BA (10% of European and North America, much rarer in China)
a. BA splenic malformation (BASM) syndrome—Association of BA, splenic anomalies (i.e. polysplenia or asplenia), vascular anomalies (e.g. preduodenal portal vein and absence of vena cava), situs inversus and cardiac anomalies. Related to maternal diabetes. Some have PKD1L1 mutations.
b. Cat eye syndrome—BA and coloboma (defect of iris), anorectal malformations and cardiac anomalies. Due to chromosome 22 aneuploidy.
c. Other more common congenital anomalies such as esophageal atresia, jejunal atresia and cardiac malformations can be associated with BA without a defined syndromic picture.
- Cystic BA (5–10%)
Characterized by an extrahepatic cyst formation in an otherwise obliterated biliary tract. Larger examples can be detected antenatally with ultrasonography.
This type may be easily confused with an obstructed choledochal malformation, the differential is intraoperative and demonstrable on cholangiography. If mucus is obtained puncturing the cyst, that is a confirmation of BA. Cholangiogram may show dilating intrahepatic ducts characteristic of a choledochal malformation.
- Cytomegalovirus associated BA (10–20%—marked worldwide variation)
This is defined by serology (IgM+ve). These infants are often associated with a later presentation and more deranged biochemical markers and a greater degrees of liver inflammation and fibrosis.
Effectiveness of Kasai portoenterostomy (KPE) and overall survival are also poor in these patients. This has been negated by specific adjuvant anti-viral therapy (e.g. ganciclovir) in some studies.
- Isolated BA
This is the largest group of patients, with heterogeneous features in terms of response to surgical management and prognosis.
Anatomical Classification
The most common anatomical classification, based on the Japanese Association of Pediatric Surgeons, divides BA in 3 categories based on the level of biliary obstruction (Fig. 36.1).
• Type 1: obstruction at the level of CBD (5–10%), often associated with cyst.
- Type 2: at the level of the CHD (rare)
- Type 3: at level of porta hepatis.
How do children with BA present?
The invariable triad of symptoms in infants with BA consists of jaundice, dark urine and pale, acholic stool.
These signs are usually present from birth, while hepatosplenomegaly and ascites secondary to portal hypertension are usually later developments.
Some may also have a coagulopathy secondary to vitamin K malabsorption and present with bleeding.
How do you diagnose BA in infants with jaundice?
The key biochemical differentiation is to determine whether there is an elevated conjugated (aka direct) bilirubin.
All surgical causes have this.
Most medical causes including “physiological jaundice” are predominantly unconjugated.
The differential diagnoses of “surgical jaundice” are: BA, choledocal malformations, inspissated bile syndrome and spontaneous perforation of the bile duct.
Ultrasonography should enable a more precise diagnosis showing intrahepatic duct dilation in all of these except for BA.
An algorithm is suggested to lead to definitive pre-laparotomy diagnosis of BA.
Although percutaneous liver biopsy is widespread, others simply opt for on-table laparoscopy or cholangiography.
ERCP is certainly possible in infancy albeit uncommonly performed.
What is the current treatment for BA?
Most infants with BA should have an attempt at restoring bile flow and abbreviating the liver damage.
The standard operation is termed Kasai portoenterostomy (KPE), but actually details of technique vary from surgeon to surgeon.
Age at KPE is important and delay is detrimental, but formerly held cut-offs values were simply naïve.
Nevertheless, beyond 100 days of age outcome suffers.
Late-presenting infants in this category may be considered for primary liver transplant certainly if cirrhotic features are obvious.
What is a Kasai portoenterostomy?
This was developed in the 1950s and 60 s in Japan by Morio Kasai and consists of excision of all apparently solid proximal bile duct remnants and Roux loop reconstruction to the denuded porta hepatis.
The length of the Roux limb is typically 40 cm.
Variations in the form of the creation of stomas in the loop are no longer done.
Frozen section of the resected part is also redundant as the principle idea of a radical resection is to excise every visible part of the biliary tract, leaving nothing behind.
Beyond using the laparoscope for diagnosis, it is possible to perform a laparoscopic approximation of a KPE [3].
Nonetheless, the only large series have been from China and Japan and caution is advised.
There is certainly no advantage, unless it is to the transplant surgeon later on!
Technical tips
• An on-table diagnosis should be clear as mostly the gallbladder is either full of clear mucus or so atrophic that a lumen can’t be found to do a cholangiogram. Bile in an intact gallbladder implies it is not BA or if it is, it is Type 1 and then a cyst should be visible.
• In case of situs inversus the operator should be on the left side.
• In case of malrotation, extra-care has to be placed in forming the Roux loop to avoid mesenteric defects which might predispose to an internal hernia. Obviously, it can no longer be retrocolic, if a Ladd’s procedure is also contemplated.
• The presence of portal hypertension can be challenging. Bipolar diathermy is the main hemostatic tool; however, this should not be applied to the transected portal plate in order to avoid bile ductule damage. Pressure or hemostatic material should suffice. Furthermore, full-thickness sutures or staples may be recommended for the jejuno-jejunal anastomosis.
How are infants managed in the post-operative period?
Prophylactic post-operative intravenous antibiotics should reflect the local microbiological policy.
Some centers continue oral antibiotics for months after though the evidence in prevention of cholangitis is weak.
The use of more specific therapy is controversial [4].
High-dose steroids (≈4–5mg/kg/day prednisolone) are widely prescribed, certainly outside of North America.
The START randomized placebo controlled trial was equivocal, but underpowered to show a “significant” difference (though there was one of 15%) [5].
Ursodeoxycholic acid is less controversial, but has no evidence base.
Anti-viral adjuvant therapy should be considered for those infants who are CMV IgM+ve.
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Postop Care:
1) Prevent inflammation within 4 weeks (monitor stool color).
2) Give/revise antibiotic to enable bilioenteric fistula.
3) Medium chain triglyceride formula milk advocated, maximize caloric input and facilitate liver absorption.
4) Steroids can be given.
Complications
1) Cholangitis withn first 2 years (bil>2.5mg/dl, acholic stools, leukocytosis, fever 38.5).
Tx: Give TMP-SMX.
2) Portal HTN
3) Splenomegaly, esophageal varices, ascites due to persistent hepatic fibrosis. Tx: Non surgical as long as hepatic function is preserved, consider liver transplant if not.
4) Hepatopulmonary syndrome
Dx: Cyanosis, dyspnea from vasoactive compounds from mesenteric circulation. Workup: ABG at room air compared to ABG at O2 supplement.
Tx: Liver transplant.
Prognosis
70% 10yr survival if KPE done withn 60days.
Better prognosis if bile ductules >150um diameter.
Poor prognosis if with associated CHD, hypersplenism, immunocompromised.
Indications for Liver transplant:
Lack of bile drain
Developmental retardation
Socially unacceptable complications.
87% 10 yr survival for living donor for liver transplant.
What complication can occur after KPE?
KPE may be completely futile and not change the level of jaundice or pigment in their stool.
Primary non-responders will need transplant consideration before 1–2years of age.
Other more specific complications may occur after KPE, including:
Cholangitis
Ascending bacterial cholangitis is described in up to 50% of the patients, usually within 2 years after KPE, then the risk diminishes. Gram negative bacteria are usually responsible and should be the target for appropriate antibiotics (e.g. meropenem, gentamicin, piperacillin-tazobactam). Clinically it presents with worsening jaundice, fever, rising inflammatory markers and altered biochemical liver function.
Portal Hypertension
Portal venous pressure is raised in >70% of infants at the time of KPE. Nevertheless, initial values correlate poorly with outcome, even development of varices. This implies that the formation of varices depends on the evolution of the fibrotic liver process following KPE rather than the condition of the liver at the time of the surgery. Endoscopic surveillance suggests endoscopically evident varices are present in 60% of patients, of which maybe half will bleed.
Acute bleeding should be treated medically at first with vasopressin or somatostatin analogues. In severe bleeding, a Sengstaken tube may have to be inserted as an emergency procedure. Endoscopic management includes banding in older children and adults while sclerotherapy is still the treatment of choice in infants.
Patients where gastrointestinal bleeding is associated with worsening liver function need evaluation for transplant.
Ascites
Ascites is often a consequence of portal hypertension but other features related to liver failure maybe involved (i.e. hypoalbuminemia and hyponatremia). Low salt diet and fluid balance management, including diuretics, are the first-line treatment. Persistent ascites may simply reflect end-stage liver failure and consideration of transplant.
Inguinal hernias
There is a higher incidence of these than the normal population possibly caused by ascites and increased abdominal pressure.
What factors affect outcome for biliary atresia?
- The state of the native liver is a key but not invariable prognostic factor. However, only cirrhosis is really detrimental and we lack real histological precision in defining this.
- Increasing age is certainly detrimental but realistically only if >80 days or the BA is clearly developmental (BASM and cystic BA).
- BA with associated anomalies has a worse outcome though whether this is because of the association with cardiac anomalies or it has an intrinsically worse outcome is not known.
- Type 1 BA and Cystic BA have the best outcome.
- Who does the operation. This is a rare disease and the porta hepatis is unfamiliar territory to most pediatric surgeons.
Centralization of resources for this disease has been adopted in many countries outside North America (e.g. UK, Finland, Netherlands).
What are the key outcome measures for Kasai Portoenterostomy?
- Median age at KPE—this reflects how quickly infants are referred in and delays in diagnosis—it should be 50–60 days;
- Proportion to clear jaundice after KPE (to normal levels <20 μmol/L or <1.5 mg/dL)—it should be >50% and values of >60–70% are possible;
- Native liver and true survival at 5 and 10 years. The former should be 45–50% with little change by 10 years, the second reflects the ease of access to safe transplantation.
Blood samples were taken from a 2 day old jaundiced neonate. Total bilirubin was 12mg/dL with a direct bilirubin of 1mg/dL. What would be the next step?
A. Coombs test
B. Phototherapy
C. Exchange transfusion
D. Biliary ultrasound
B. Phototherapy
Regarding the type and classification of biliary atresia, which of the following is false?
A. Type I atresia at porta is the most common.
B. Type I is the obliteration of the common bile duct, while the proximal bile ducts are patent.
C. Type IIa is atresia of the hepatic duct, with cystic bile ducts found at the porta hepatis.
D. Type IIb is atresia of the cystic duct, common bile duct, and hepatic ducts.
E. Type III is involvement of the extrahepatic biliary tree and intrahepatic ducts of the porta hepatis.
A
Type III atresia at portahepatis is the most common, about 88 percent.
Syed/MCQ
In preoperative management of biliary atresia, what is not required?
A. Chloretics
B. Antibiotic
C. Upper GIT contrast study
D. Metabolic and nutritional care
D. Essential fatty acid supplement
C
Upper GIT contrast study is generally not required.
Syed/MCQ
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Preoperative care:
1) Cephalosphorin+aminoglycoside 1 hr prior to OR, continued postoperatively until WBC resolved or CRP <0.3, or prophylactically if without cholangitis.
2) Vitamin K supplementation IV for several days prior.
3) Bowel prep glycerin enemas
4) NPO x 24 hrs
5) Broad spectrum antibiotics 1hr before skin incision.
6) Cholagogues ursocholic or aminoethylsulfuric at day 5 postop.
Select the best answer about the causes/cause of cholangitis after surgery for biliary atresia.
A. Portal venous infection
B. Destruction of lymphatics at porta hepatis
C. Bacterial translocation
D. All of the above
E. None of the above
D
All of the above.
Syed/MCQ
Regarding complications of surgery for biliary atresia, which of the following statements is false?
A. Cholangitis
B. Portal hypertension
C. Stricture of anastomosis
D. Leakage of anastomosis and peritonitis
E. None of the above
E
A, B, C and D all statements are true.
Syed/MCQ
The best answer among the following regarding differential diagnosis of biliary atresia is:
A. Biliary hypoplasia
B. Choledochal cyst
C. Inspissated bile syndrome
D. Neonatal jaundice
E. All of the above
E
Differential diagnosis also includes neonatal hepatitis, acquired obstruction like external pressure or stone, glycogen storage disease, lysosomal storage disease, G6PD deficiency and hemolytic disease.
Syed/MCQ
Regarding the management of biliary atresia, which of the following is false?
A. Preoperative presence of the gallbladder is an indication for cholangiography.
B. Preoperative gallbladder is used as a guide.
C. In Roux-en-y portoenterostomy, a 20cm Roux-en-y loop, 10cm distal to the duodenal junction is used.
D. Preoperative biopsy is taken from the right lobe.
E. If biopsy shows ductiles >150micro-m, this indicates a good prognosis.
C
20 cm loop is too short; about 40 cm loop of jejunum is used.
Syed/MCQ
What is the etiology of biliary atresia?
The exact etiology of biliary atresia is unknown and likely multifactorial. Theories implicating genetic, inflammatory, and infectious causes have been presented, but none has been proven.
The higher incidence of biliary atresia in certain populations makes a genetic cause plausible. Moreover, the observation that up to 20% of biliary atresia cases are associated with other congenital malformations implies a global developmental abnormality that may be under genetic control. Despite this, the occurrence of biliary atresia in twins is exceedingly rare, familial patterns have not been seen, and a clear genetic cause has not been found.
Theories suggesting an acquired, infectious etiology are supported by several findings. First, several viruses such as reovirus and rotavirus have been proposed as possible infectious agents responsible for the development of biliary atresia. Animal models of perinatal viral infection produce biliary atresia, although consistent viral isolation has not been possible in human cases. In addition, given the high prevalence of these viruses, it would be expected that the incidence of biliary atresia would be higher if, in fact, viral infection was causative.
Second, it appears that many cases of biliary atresia are acquired rather than congenital. Up to 60% of infants who are found to have biliary atresia have been documented as having pigmented stools sometime during the postnatal period.
Third is the epidemiologic finding of seasonal clustering of biliary atresia cases during the winter months in some studies.
Other proposed factors associated with biliary atresia include bile duct ischemia, abnormal bile acid metabolism, pancreaticobiliary maljunction, and the effect of certain environmental toxins.
[Coran]
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Various etiologic mechanisms for BA have been proposed, including intrauterine or perinatal viral infection, immunologically mediated inflammation and other autoimmune/ genetic factors, exposure to toxins, abnormal ductal plate remodeling, a vascular or metabolic insult to the developing biliary tree, and pancreaticobiliary malunion. Kilgore and Mack reported the most recent investigations into the pathogenesis of BA.
Reovirus type 3 infection, rotavirus, CMV, papillomavirus, and Epstein–Barr virus have all been proposed as possible etiologic agents, but conclusive evidence is lacking. In one report, CMV infection was found in 4 of 10 patients with BA, and reovirus infection has been found in the livers of up to 55% of patients with BA versus 10–20% in a control group. Evidence for a viral etiology in children with BA is inconsistent in the literature, although several viruses have been used to create animal models that may be valuable for assessing the pathogenesis and treatment of BA.
Generally, BA is not considered an inherited disorder. However, genetic mutations that result in defective morphogenesis may be important in syndromic BA that is associated with other congenital anomalies, including interrupted inferior vena cava, preduodenal portal vein, intestinal malrotation, situs inversus, cardiac defects, and polysplenia, likely due to a developmental insult occurring during differentiation of the hepatic diverticulum from the foregut of the embryo. Mutations of the CFC1 gene, which is involved in left–right axis determination in humans, have been identified in a few patients with syndromic BA.
Transgenic mice with a recessive deletion of the inversin gene have situs inversus and an interrupted extrahepatic biliary tree. The importance of the macrophage migration inhibitory factor gene, which is a pleiotropic lymphocyte and macrophage cytokine in BA pathogenesis, also has been reported. Other studies have identified abnormalities in laterality genes in a small number of patients with BA, including the transcription factor ZIC3. A high incidence of polymorphic variants in the jagged-1, keratin-8, and keratin-18 genes have also been described in a series of 18 children with BA. Taken together, the increased incidence of nonhepatic anomalies in children with BA and genetic mutations reported in subsets of patients with laterality defects suggest that multiple genes are involved, each affecting a small number of patients.
Intrahepatic bile ducts are derived from primitive hepatocytes that form a sleeve (the ductal plate) around the intrahepatic portal vein branches and associated mesenchyme early in gestation. Remodeling of the ductal plate in fetal life results in the formation of the intrahepatic biliary system. This is supported by similarities in cytokeratin immunostaining between biliary ductules in BA and normal first-trimester fetal bile ducts. These findings suggest that nonsyndromic BA might be caused by a failure of bile duct remodeling at the hepatic hilum, with persistence of fetal bile ducts poorly supported by mesenchyme.
Several studies have investigated whether bile duct epithelial cells are susceptible to an immune/inflammatory attack because of abnormal expression of human leukocyte antigens (HLAs) or intracellular adhesion molecules on their surfaces. A greater than threefold increase in the HLA-B12 antigen has been found in babies with BA compared with controls, particularly in those with no associated malformations. 51 Aberrant expression of class II HLA-DR antigens on biliary epithelial cells and damaged hepatocytes in patients with BA may render these tissues more susceptible to immune-mediated damage by cytotoxic T-cells or locally released cytokines. Increased expression of intercellular adhesion molecule-1 (ICAM-1) has been noted on bile duct epithelium in patients with BA, a finding that may play a role in immune-mediated damage. Strong expression of ICAM-1 also has been found on proliferating bile ductules, endothelial cells, and hepatocytes in BA. A direct relationship exists between the degree of ductal expression of ICAM-1 and disease severity, suggesting that ICAM-1 might be important in the development of cirrhosis.
Interest has also focused on co-stimulatory molecules. Two processes are involved in the activation of Tlymphocytes by antigen-presenting cells. One relates to the expression of major histocompatibility complex class II molecules, which interact directly with T-cell receptors. The other depends on the expression of B7 antigens on antigen-presenting cells and provides the second (costimulatory) signal to T-lymphocytes through CD28. In postoperative BA patients with good liver function, co-stimulatory antigens (B7-1, B7-2, and CD40) are expressed only on bile duct epithelial cells, whereas in patients with failing livers these markers are found on the surfaces of Kupffer cells, dendritic cells, and sinusoidal endothelial cells, and in the cytoplasm of hepatocytes. This finding suggests that the biliary epithelium and hepatocytes in BA are susceptible to immune recognition and destruction. Agents that block or prevent co-stimulatory pathways might offer a new therapeutic approach for reducing liver damage.
Two studies have involved comprehensive molecular and cellular surveys of liver biopsies and found a proinflammatory gene expression signature, with increased activation of interferon-γ, osteopontin, tumor necrosis factor-α, and other inflammatory mediators. These studies may prove to be helpful in delineating the molecular networks responsible for the proinflammatory response and autoimmunity thought to be involved in the pathogenesis of BA. However, none of these mechanisms appear to be mutually exclusive, and it is not clear which signs and symptoms are primary and which are secondary.
Most recently, DNA hypermethylation of Foxp3 was reported in BA infants, as well as a mouse model of BA. Klemann et al. showed that γδ T-cells were high producers of interleukin-17 (IL-17), and blocking IL-17 resulted in decreased liver inflammation and serum bilirubin levels. Furthermore, liver tissue from patients with BA at diagnosis had significantly increased levels of IL-17 mRNA. Lages et al. showed that CD4+ T cells were primarily responsible for IL-17 production and IL-17 stimulated macrophage influx and biliary injury in a mouse model.
In summary, the etiology of BA remains unknown. However, current research suggests there is a complex interplay of genetic predisposition, virus triggers, and progressive autoimmunity, culminating in bile duct injury, fibrosis, and biliary cirrhosis. A clearer understanding of the factors associated with bile duct epithelial injury will provide a framework for future targeted therapeutic interventions aimed at protecting the intrahepatic biliary system from ongoing injury.
[Holcomb and Ashcraft]
What is the embryology of the biliary system?
The biliary system originates from the hepatic diverticulum of the foregut at 4 weeks of gestation.
This structure differentiates into cranial and caudal components, which give rise to the intrahepatic and extrahepatic bile ducts, respectively.
It is during this period that the bile ducts undergo recanalization, eventually leading to an intact biliary tree.
Errors in the recanalization process constituted early theories regarding the etiology of biliary atresia, but this is no longer believed to be correct.
[Holcomb and Ashcraft]
What are the expected histopathologic findings for biliary atresia?
Early in the course of BA, the liver becomes enlarged, firm, and green. The gallbladder may be small and filled with white mucus, or it may be completely atretic.
Microscopically, the biliary tracts contain inflammatory and fibrous cells surrounding minuscule ducts, which are probably remnants of the original embryonic duct system.
The liver parenchyma is fibrotic and shows signs of cholestasis.
Proliferation of biliary neoductules is seen.
This process develops into end-stage cirrhosis if adequate biliary drainage does not occur.
These early changes are often nonspecific and may be confused with neonatal hepatitis and metabolic diseases.
It is generally accepted that the pathologic changes seen in BA are panductal, affecting the intrahepatic biliary tree as well as the extrahepatic bile duct system.
Intrahepatic bile ducts may be narrowed, distorted, or irregular.
Proliferation most likely results from disturbances in formation of the ductal plate as well as ductular metaplasia of hepatocytes.
Some authors think damage to the extrahepatic biliary system is a secondary phenomenon caused by obliteration. This theory is strongly supported by the fact that outcome is better if hepatic portoenterostomy is performed early.
The intrahepatic biliary tree is important not only pathologically, but also clinically.
The degree of damage that has already occurred in the intrahepatic biliary system is actually responsible for much of the morbidity after hepatic portoenterostomy.
[H&A]
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The pathologist plays a central role in the diagnosis of biliary atresia and provides an Important assessment of structures present at the fibrous biliary remnant.
Inflammation is invariably seen in liver biopsies and in resected specimens.
In the appropriate clinical scenario, a percutaneous liver biopsy can reliably aid in the diagnosis of biliary atresia.
The finding of bile ductular proliferation in the liver biopsy is considered diagnostic for biliary atresia.
Associated findings often include bile stasis, periportal inflammation, identification of giant cells, and varying degrees of fibrosis.
Histologic evaluation of the fibrous remnant can reveal patency or partial patency of ductal structures or complete absence of these structures. This may depend on whether excision of the remnant occurred before or after inflammatory obliteration of the extrahepatic ducts.
Identifiable structures that can be found in the biliary remnant include bile ducts, collecting ductules, and biliary glands. Of these, the ductules are ultimately responsible for bile drainage after the portoenterostomy procedure and, over time, these can form stable bile conduits.
[Coran]
How is biliary atresia diagnosed?
Signs suggestive of BA are jaundice, pale stools, and hepatomegaly. Meconium staining may be normal and feces may be yellow during the neonatal period in more than half of patients, but the urine gradually turns dark brown.
Although infants may be active and grow normally, anemia, malnutrition, and growth retardation ensue because of malabsorption of nutrients and fat-soluble vitamins.
Jaundice that persists beyond 2 weeks should no longer be considered physiologic, particularly if the elevation in bilirubin is mainly in the direct fraction.
Neonatal hepatitis and interlobular biliary hypoplasia are the most likely differential diagnoses and must be excluded.
Conventional liver function tests (LFTs) alone cannot be used to diagnose BA.
Although a number of diagnostic protocols have been published, the importance of early diagnosis cannot be overemphasized.
A definitive diagnosis of BA requires further investigations, including special biochemical studies, tests to confirm the patency of the extrahepatic bile ducts, and needle biopsy of the liver.
Many surgeons consider liver biopsy to be the most reliable test for establishing the diagnosis.
Serum lipoprotein-X is positive in all patients with BA, although it also may be positive in 20–40% of patients with neonatal hepatitis.
Serum bile acid levels increase in infants with cholestatic disease, but both the total bile acid level and the ratio of chenodeoxycholic acid to cholic acid have no value for differentiating BA from other cholestatic diseases.
Standard serum “liver function tests” are uniformly obtained, but specificity is lacking. In biliary atresia both the direct and indirect bilirubin levels are elevated. The transaminases are also mildly to moderately increased. Alkaline phosphatase levels are often elevated in infants and children due to contribution from bone remodeling. For this reason, the gammaglutamyl transpeptidase (GGTP) level can be used as a more specific indicator of hepatobiliary disease. Unless decompensated liver disease is present, tests of hepatic synthetic function such as the clotting cascade and serum albumin are normal.
In order to rule out conditions that can mimic biliary atresia, screening for perinatal infections due to members of the TORCH family (Toxoplasmosis, Other viruses, Rubella, Cytomegalovirus, and Herpes Simplex Virus) should be performed. In addition, screening for the presence of alpha-1 antitrypsin deficiency should occur.
Hyaluronic acid, which has been considered a serum marker for liver function, has also been reported to be a biochemical marker for evaluating infants with BA.
Duodenal aspiration is an easy, noninvasive, and rapid test because BA can be excluded if bilirubin-stained fluid is aspirated. Intubation of the duodenum via the nasoduodenal route with aspiration or prolonged collection of duodenal fluid can exclude biliary atresia if bile-stained fluid is obtained. Although simple, this test is invasive, subjective, and similar in concept to the DISIDA scan, which is easily obtained in most centers.
Hepatobiliary scintigraphy with technetium-labeled agents is widely used for differentiating BA from other cholestatic diseases.
In BA, uptake by hepatocytes is rapid, but excretion into the bowel is absent, even on delayed images. In hepatocellular jaundice, uptake is delayed owing to parenchymal disease and intestinal excretion may be present or absent.
Ultrasonography (US) should be performed on all jaundiced infants. Hepatobiliary US will exclude other surgical causes of jaundice such as choledochal cyst and inspissated bile syndrome.
In BA, the intrahepatic ducts are not dilated because they are affected by an inflammatory process. Various sonographic features have been targeted in an attempt to distinguish BA from other causes of conjugated hyperbilirubinemia in infants.
In BA, the gallbladder is small, shrunken, and noncontractile, and there is increased echogenicity of the liver.
The presence of other associated anomalies of the polysplenia syndrome is pathognomonic of BA.
Differentiation from choledochal cyst and type I BA also is rapid and simple with US.
Irrespective of interobserver variation, failure to visualize the common bile duct is not diagnostic of BA because a patent distal common bile duct may be found in up to 20% of BA patients. However, an absent gallbladder or one with an irregular outline is suggestive of BA.
In some cases, a well-defined triangular area of high-reflectivity echogenicity is seen at the porta hepatis, corresponding to fibrotic ductal remnants (the “triangular cord” sign). A recent meta-analysis found that the triangular cord sign and gallbladder abnormalities are the two most accurate and widely accepted US findings currently used for the diagnosis or exclusion of BA.
In other words, a combination of the triangular cord sign and gallbladder anomalies improves diagnostic sensitivity, whereas the absence of a common bile duct, enlargement of the hepatic artery, and the presence of hepatic subcapsular blood flow are less valuable findings for diagnosis. In fact, meticulous US focusing on the presence of the triangular cord sign and gallbladder anomalies might reduce the need for liver biopsies and hepatobiliary scintigraphy in infants suspected of having BA.
Nonvisualization of the fetal gallbladder on routine gestational US may be suggestive of a range of anomalies ranging from gallbladder agenesis to BA.
Amniotic fluid digestive enzymes, which are synthesized by the biliary epithelium, gradually decrease until 24 weeks of gestation.
As it is no longer possible to differentiate between abnormally low and physiologically low levels of the enzymes after 24 weeks of gestation, the prenatal diagnosis of BA is difficult.
The most conclusive technique to differentiate among BA, biliary hypoplasia, and severe neonatal hepatitis is direct observation of the porta hepatis using laparotomy or laparoscopy with or without cholangiography.
Laparoscopy-assisted cholangiography is also an option, as is percutaneous cholecystocholangiography, if an open approach to diagnosis is stressful to parents of infants with cholestasis that may be caused by a disease other than BA.
Most patients with BA can be diagnosed accurately by using an appropriate combination of the above-mentioned investigations.
How should biliary atresia patients be managed preoperatively?
Infants with presumed biliary atresia should be prepared for exploration soon after diagnostic testing has been completed. Standard presurgical measures should be taken and, in general, children can be admitted on the day of surgery.
Preoperative blood tests should include complete blood count, coagulation profile, and LFTs.
1) Vitamin K supplementation
Although most infants diagnosed with biliary atresia will have normal coagulation studies, poor absorption of the fat-soluble vitamin K can theoretically render them functionally vitamin K deficient. Most patients with BA have abnormal LFT results and vitamin K deficiency by the time of diagnosis.
All infants should have parenteral vitamin K2 supplementation for several days before exploration. If possible, preoperative oral supplementation with fat-soluble vitamins (A, D, E, and K) or an intramuscular injection of vitamin K (1 mg) should be considered.
2) NPO: Patients should be nil by mouth for 24 hours prior to surgery.
3) Bowel preparation (if performed) should commence with oral kanamycin and glycerin enemas to decrease abundant colon microbiota to minimize intestinal gas.
4) Parenteral broad-spectrum antibiotics should be administered preoperatively just before the skin incision (Cephalosporin + Aminoglycoside 1h prior to incision, continued postop until WBC resolves or CRP < 0.3; May use prophylactically if without cholangitis)
What congenital anomalies are associated with biliary atresia?
Malrotation
Preduodenal portal vein
Polysplenia
Interrupted inferior vena cava
Azygous continuation
Cardiac malformations
How is hepatobiliary scintigraphy performed in the evaluation of biliary atresia?
Hepatobiliary scintigraphy relies on the use of isotopes of technetium 99m to assess excretion of bile from the liver into the small intestine and therefore biliary patency.
The term “HIDA” (hydroxy iminodiacetic acid) scan is often used, but the technetium-labeled compound diisopropyl iminodiacetic acid (DISIDA) is more effective in the presence of significant cholestasis and therefore more commonly used.
The usefulness of all hepatobiliary scintigraphy is diminished in the presence of severe jaundice, and this may cause errors in interpretation.
If time allows, all jaundiced infants undergoing hepatobiliary scintigraphy should be pretreated with phenobarbital (5 mg/kg/day) for 5 days before the study.
Presence of isotope in the intestine immediately confirms patency of the biliary system, and the diagnosis of biliary atresia can be excluded.
Excretion of isotope may be delayed, however, in the presence of liver dysfunction. For this reason, a delayed assessment of isotope excretion at 24 hours is warranted.
When no isotope is seen in the intestine after 24 hours, biliary obstruction is presumed and the diagnosis of biliary atresia must be further pursued.
What is the value of liver biopsy in the diagnosis of biliary atresia?
A percutaneous liver biopsy can help differentiate biliary atresia from other cholestatic conditions with a high degree of reliability and should be considered the most accurate nonsurgical diagnostic test.
It is the most invasive of the diagnostic modalities but can be performed safely by an experienced pediatric hepatologist, or, if needed, by the surgeon.
Typically, examination of several portal tracts by a well-trained pathologist will reveal important findings that can confirm or exclude biliary atresia.
The presence of varying degrees of inflammation with ductular proliferation is considered compatible with the diagnosis of biliary atresia because these findings are not seen in other nonobstructive cholestatic syndromes.
Further findings of bile stasis with plugging and giant cell transformation further support the diagnosis of biliary atresia.
On the basis of the appearance of the liver biopsy, bile duct paucity syndromes can be readily differentiated from biliary atresia.
In contrast, however, it can be difficult to differentiate between parenteral nutrition-associated cholestasis and biliary atresia on the basis of liver biopsy alone.
This distinction should be made on the basis of the overall clinical assessment or, on rare occasions, at exploration when the diagnosis cannot be confirmed preoperatively.
What is the surgical treatment for biliary atresia?
The Roux-en-Y hepatic portoenterostomy procedure (Kasai Procedure) is the standard initial operation for treatment of infants with biliary atresia.
The operation involves excision of the entire extrahepatic biliary tree with transection of the fibrous portal plate near the hilum of the liver.
Bilioenteric continuity is then reestablished with a Roux-en-Y limb.
The ultimate goal of the procedure is to allow drainage of bile from the liver into the Roux limb via microscopic ductules in the portal plate. The conduct of the operation is described as follows.
The infant should be placed supine and on an operating table that will permit operative cholangiography, if deemed necessary. The exploration begins via a right upper abdominal incision. The left upper quadrant is examined, first searching for the spleen. Absence of the spleen or the finding of polysplenia can alert the surgeon to the presence of important associated anomalies such as malrotation, preduodenal portal vein, and interrupted inferior vena cava with azygous continuation.
During evaluation of the left upper quadrant, adequate position of the tip of the nasogastric tube is also confirmed and the tube is secured by the anesthesiologist.
Next, the liver, biliary structures, and porta are inspected. The liver in biliary atresia can appear nodular and fibrotic with a greenish color. This finding is not common in neonatal hepatitis or bile duct paucity syndromes, where the liver is smooth and dark brown in color. Many infants with biliary atresia have a contracted, fibrotic gallbladder. If a rudimentary fibrous gallbladder is noted at initial exploration and if it clearly has no lumen, then the diagnosis of biliary atresia has been confirmed and the operation can proceed with dissection of the portal plate.
If the gallbladder is normal-appearing, or if it is felt to have a lumen, then additional intraoperative diagnostic maneuvers are warranted before dissecting the portal plate. In this situation, a purse-string suture can be placed in the fundus of the gallbladder and the fluid within the lumen of the gallbladder aspirated with an angiocath. If clear fluid (white bile) returns, then our approach has been to proceed with portal plate dissection without a cholangiogram. If, however, the aspirated fluid is darker in color or if there is any ongoing question regarding the diagnosis, then a cholangiogram should follow.
Although simple in concept, the cholangiogram can be difficult to perform and interpret successfully during this exploration. The following steps can be used to maximize the diagnostic yield of the intraoperative cholangiogram. First, a secure purse-string suture should be placed. A second purse-string suture can also be placed to prevent contrast leakage. Either an angiocath or a laparoscopic cholangiogram catheter can be placed into the lumen of the gallbladder before tying the purse-string suture(s). Diatrizoic acid (Hypaque or Gastrografin) is diluted 1:1 with normal saline and injected as the contrast agent via the cholangiogram catheter to assess for patency or obstruction of the biliary tree. Real-time, live fluoroscopy facilitates rapid intraoperative interpretation of the study. If contrast flows freely into the duodenum and into intrahepatic bile ducts, then patency of the biliary tree has been established and the diagnosis of biliary atresia excluded.
In this scenario, a wedge liver biopsy should be performed, the cholangiogram catheter removed, the cholecystotomy closed, and the operation concluded.
On occasion, contrast will flow freely into the gallbladder and down the distal common bile duct into the duodenum but not proximally into the intrahepatic bile ducts. This finding should be confirmed by occluding the distal common bile duct with an atraumatic “bulldog” clamp and reinjecting the cholangiogram catheter. This maneuver may encourage preferential filling of any patent proximal ducts that may have initially failed to opacify with contrast material when the distal resistance to flow was low. It is important to inject contrast gently because a speedy injection under pressure is likely to cause leakage of contrast around the purse-string suture, resulting in an obscured and confusing cholangiogram. Failure to delineate patent intrahepatic and extrahepatic biliary structures mandate that the surgeon proceed with portal dissection.
Regardless of the presence of a patent gallbladder or distal common bile duct, a direct Roux-en-Y hepatic portoenterostomy affords outcomes that are superior to other forms of reconstruction such as the portocholecystostomy. Some surgeons gain exposure by dividing both triangular ligaments, thereby exteriorizing almost the entire liver. This step is not necessary and likely disrupts lymphatics that may be responsible for the development of ascites. We have found that upward retraction of the liver to expose the porta affords excellent visualization of the critical structures and can be accomplished by assigning an assistant for retraction in the right upper surgical field or by carefully placing a fixed metal retractor with upward traction.
The peritoneum overlying the hepatoduodenal ligament is opened to allow identification of the structures in this area. The fibrous remnant of the distal common bile duct is often present here. It can be identified in the anterolateral aspect of the hepatoduodenal ligament, isolated and divided. Care should be taken to avoid injury to aberrant hepatic arteries that may be nearby. With traction on the cut end of the obliterated distal common bile duct, the fibrous biliary remnant can be dissected toward the porta. It is often necessary to dissect the right and left hepatic arteries away from the field in order to preserve them. During this dissection, the gallbladder remnant is also dissected away from the liver in continuity with the rest of the extrahepatic biliary remnant.
As dissection continues proximally, the biliary remnant develops into a cone of fibrotic tissue that is located at the bifurcation of the main portal vein into its left and right branches. This constitutes the most important landmark during the dissection of the portal plate and should be the goal of every dissection.
In this location it may be necessary to control several small portal vein branches to avoid inadvertent injury with subsequent bleeding. The absence of identifiable biliary remnant tissue or the finding of poor quality tissue at the expected location of the portal plate sometimes confuses the dissection. As stated earlier, the bifurcation of the portal vein should be used as a landmark and is especially important in such cases where the biliary remnants and portal plate are difficult to identify clearly.
Once the fibrous cone and portal plate region have been identified, the fibrous cone is placed on gentle traction and transected with sharp scissors or a knife. It is not beneficial to cut deeply toward the liver parenchyma because this may result in more scar formation and inhibition of bile drainage. Bleeding at the transected portal plate is controlled with pressure and placement of a surgical sponge in the area. Use of cautery on the portal plate is discouraged and should be minimized because this structure contains the fine ductules needed for success of the procedure.
The resulting surgical specimen should be marked and submitted for routine pathologic evaluation. Careful measurement of the diameter of any biliary ductules by an experienced pathologist should be requested because this may provide important prognostic information. Although advocated by some, we have not found frozen section to be helpful in guiding the level of transection.
With a completed portal plate dissection, the operation shifts to the construction of the Roux limb. The proximal jejunum is identified and transected about 10 centimeters distal to the ligament of Treitz. The distal end, destined for the right upper quadrant, is oversewn and the Roux limb is measured to 40 to 50 centimeters. (Roux limb should be short enough as to not cause roux limb stasis).
At this location, an end-to-side jejunojejunostomy is created with interrupted absorbable sutures. The oversewn end of the Roux limb is carefully brought into the right upper quadrant via a small defect created in the avascular portion of the transverse mesocolon.
The side of the Roux limb is opened, and the portoenterostomy is created. The posterior suture line is placed first using 6-0 absorbable suture with knots tied inside the lumen. Placement of these sutures must be exact with care taken to avoid injuring or impinging on the portal tissue. Once this posterior row is complete, the anterior sutures can be placed using similar care and precision. When complete, the entire surface of the portal plate must be contained within the jejunal lumen of the Roux limb. In this way, any bile drainage via biliary ductules at the portal plate will be contained within the Roux limb and proceed distally.
Before closure, it is advisable to close the mesenteric defect created by construction of the Roux limb and to anchor the Roux limb to the edges of the defect in the transverse mesocolon. These maneuvers are aimed at preventing internal herniation and at keeping the Roux limb in the right upper quadrant and without tension.
A small closed suction drain is placed near the portoenteric anastomosis, and a wedge liver biopsy is routinely performed but likely not absolutely necessary. The abdomen is then closed using standard techniques.
When is primary Liver transplantation indicated in BA?
Some investigators have proposed that primary liver transplantation be considered the initial treatment for infants with biliary atresia, citing deleterious effects of the Kasai procedure on subsequent liver transplantation, if needed.
This approach, however, would subject a percentage of children to the dangers of transplantation and its associated short- and long-term complications who would have been cured by the Kasai procedure.
For this reason, primary liver transplantation has been reserved for selected cases such as delayed diagnosis with severe liver failure where a Kasai procedure would be risky and have a high failure rate.
For all other children with compensated liver function and a timely diagnosis, the Kasai procedure and liver transplant are considered by most to be sequential, complementary procedures.
[Coran]
—
Primary transplantation for BA has been reported. Incidence varies from 0.1% (Japan), 3% (Netherlands and the United Kingdom), 4% (France), 10% (Canada and Switzerland), and 11% (Germany).
Primary liver transplantation for BA has excellent results but is performed rarely. A treatment dilemma exists for the approximately one-third of infants with BA who derive no benefit from a Kasai portoenterostomy.
If these patients could be identified with specific multidisciplinary protocols, they could be prepared directly for primary liver transplantation without having more traditional surgical intervention.
[H&A]
What are the indications for liver transplantation following portoenterostomy?
The indications for liver transplantation following portoenterostomy are:
(1) lack of bile drainage;
(2) signs of developmental retardation or its sequelae; and
(3) presence of socially unacceptable complications/side effects.
A high hepatic artery resistance index measured on Doppler US is an indication for relatively urgent transplantation.
Deterioration in hepatic status may be precipitated by adolescence or pregnancy. However, in our experience, less than 10% of patients undergoing portoenterostomy will remain jaundice free and reach adulthood with good liver function.
The dramatic improvement in survival with the use of cyclosporine and tacrolimus immunosuppression after liver transplantation raises the question of transplantation becoming a more conventional form of treatment for BA.
Donor supply is a problem, alleviated to some extent by reduced-size liver transplantation (split-liver grafting) and living-related liver transplantation.
Five-year survival after liver transplantation for BA is currently 80–90%, and long-term studies of post-transplant BA patients have shown that survivors have an acceptable to good quality of life.
A study summarized the largest series (n = 464) of postportoenterostomy patients who had undergone living-related liver transplantation. The outcome of living-related liver transplantation in adults with BA was significantly worse than in infants and children. The overall 5- and 10-year survival rates were 70% and 56% in adults versus 87% and 81% in infants and children, respectively.
In contrast, there is another report that concluded that living-related liver transplantation can be performed safely after portoenterostomy in adults with long-term survival rates similar to those for pediatric patients.
Longer immunosuppression might ultimately lead to increased morbidity, including higher rates of cancer, infection, and metabolic diseases later in life. In addition, in living-related liver transplantation, the risk to the donor is always a concern.
The optimal timing of transplantation in postportoenterostomy patients has yet to be established.
Recently, Kasahara et al. published a summary of living-donor liver transplantation for patients with BA in Japan. They reported that the 1-, 5-, 10-, 15-, and 20-year survival rates for patients and grafts undergoing living-donor liver transplantation for BA were 91.6, 91.5, 87.1, 85.4, and 84.2% and 90.5, 90.4, 84.6, 82.0, and 79.9%, respectively.
According to data from the Japanese Liver Transplantation Society, there were significant differences in survival rates between patients and grafts.
Multivariate analysis showed that donor body mass index, ABO incompatibility, graft type, recipient age, center experience, and transplant era were prognostic for a better overall graft survival.
What are the major determinants for satisfactory outcomes after portoenterostomy?
Without question, the Kasai hepatic portoenterostomy has greatly improved outcomes of infants with BA, and the results of surgical treatment have improved steadily over the past 30 years.
Classically, the major determinants of satisfactory outcome after portoenterostomy are:
(1) age at initial operation,
(2) successful achievement of postoperative bile flow,
(3) presence of microscopic ductal structures at the porta hepatis,
(4) the extent of liver parenchymal disease at the time of diagnosis, and
(5) technical factors involving the portoenterostomy anastomosis.
Age at portoenterostomy is the single most widely quoted prognostic variable.
A favorable outcome is expected if hepatic portoenterostomy is performed before 60 days of age because cirrhosis will usually develop by 3–4 months of age.
However, a wide discrepancy exists in reported long-term results. One study from Japan found postoperative outcome to be excellent, with a 10-year survival rate of more than 70% if the portoenterostomy was performed before 60 days of age. However, a nationwide survey of the Surgical Section of the American Academy of Pediatrics in the United States found that long-term survival was only 25%. Other reported 10-year survival rates include 40–50% from the United Kingdom and 68% from France.
Outcomes are considerably worse if patients are older than 100 days at the time of portoenterostomy because obliterative cholangiopathy and hepatic fibrosis have likely already developed.
The impact of age at portoenterostomy on long-term outcome, especially in patients with type III BA, has been studied. Age at portoenterostomy was found to have a significant impact on jaundice clearance, but not on longterm survival in type III BA, suggesting that age at portoenterostomy may have less relevance as a prognostic factor over time. In another study from Hong Kong, a high percentage of patients achieved good bile flow and normal postoperative bilirubin levels despite portoenterostomies being performed after the age of 60 days with no suggestion of poor outcome.
Of interest is a report by Kuroda et al., who reviewed postoperative BA patients in relation to pregnancy and found that age at portoenterostomy may not necessarily influence long-term outcome. However, liver function at puberty may be a useful indicator and may be predictive for the safety of pregnancy. Also, management strategies may need to be revised accordingly after puberty.
Whether the ductules at the liver hilum are obliterated or present in babies with BA does not seem to be indicative of prognosis. Some patients with microscopic ducts may have a good outcome, and patients with larger ducts may not do as well.
Types I and II BA generally have a good prognosis if treated early.
In the more typical type III disease, the presence of larger bile ductules at the porta hepatis (>150 μm in diameter) is associated with a better prognosis.
The subgroup of infants with syndromic BA have worse outcomes in terms of both clearance of jaundice and survival.
The latter is related to associated malformations (particularly congenital heart disease), a predisposition to developing hepatopulmonary syndrome, and possible immune compromise from functional hyposplenism.
Personal experience suggests that infants with concomitant CMV infection fare less well after a portoenterostomy.
The importance of surgeon experience was shown in a British survey in which patients who underwent portoenterostomy at centers treating 1 case per year had significantly worse outcomes than patients who were treated at centers performing more than 5 cases per year.
Since 1999, the management of BA has been centralized to three centers in England and Wales that are able to offer both portoenterostomy and transplantation. In 2011 the results of this policy change were reported, and it was found that outcomes were better, probably due to centralization of surgical and medical resources.
Recently, outcomes in infants enrolled in the prospective Childhood Liver Disease Research and Education Network who underwent portoenterostomy were reported. Liver anatomy, splenic malformation, presence of ascites, liver nodularity at portoenterostomy, and early postoperative clearance of jaundice were found to be significant predictors of transplant-free survival.
Irrespective of age and other factors related to the timing of portoenterostomy, a significant decrease in serum bilirubin and signs of good bile excretion in the stool may be predictive of good long-term outcome.
Due to the possibility of sudden hepatic deterioration and the constant concern for cholangitis and portal hypertension, recent reports about long-term outcomes in BA patients consistently emphasize lifelong follow-up.
Growth failure and poor mean weight z-scores 3 months after hepatoportoenterostomy are associated with poor outcome.
A BA registry inaugurated in Japan in 1989 now has input from some 3160 patients. Of these, 1236 patients have undergone liver transplantation and continue to be followed with standardized questionnaires. Twenty-year survival rates are 89% overall and 49% with native livers.
The prognosis of BA has markedly improved owing to surgical intervention involving Kasai portoenterostomy and liver transplantation.
According to a recent report from the Japanese Biliary Atresia Registry, the age at Kasai portoenterostomy had a significant impact on long-term native liver survival. The best jaundice clearance rates and best longterm native liver survival rates were achieved in patients who underwent portoenterostomy as neonates. Long-term native liver survival rates were well correlated with age at portoenterostomy.
Certain substances can act as prognostic factors in BA. Serum levels of IL-6, IL-1ra, insulin-like growth factor-1 (IGF-1), vascular cell adhesion molecule-1 (VCAM-1), and ICAM-1 correlate with liver dysfunction in postoperative BA patients.
Immunohistochemically, a reduction in the expression of CD68 and ICAM-1 at the time of portoenterostomy is associated with a better prognosis.
The presence of ductal plate malformation in the liver predicts poor bile flow after hepatoportoenterostomy.
How are biliary atresia patients managed postoperatively?
Drainage of gastric secretions with a nasogastric tube should continue for the first 48 hours, and the tube can usually be removed at this point.
By the second or third postoperative day, infants often have already passed gas and stool and an oral diet can be started.
Intravenous antibiotics are administered until the child begins feeding, and this is subsequently converted to long-term oral antibiotics that are continued at discharge.
The closed suction drain is removed before discharge, typically on the fifth postoperative day.
Antibiotics, a choleretic agent, fat-soluble vitamin supplements, and an oral steroid taper have been the routine for our group, although the support for the use of steroids is not universal as discussed in the next section.
CORTICOSTEROIDS
The role of corticosteroids is controversial, but we strongly believe they are choleretic and decrease inflammation and scarring at the anastomosis site.
The use of adjuvant steroids following portoenterostomy for BA remains controversial. Davenport et al. performed the first randomized, placebo-controlled, double-blinded study using a low-dose 6-week course of oral prednisolone starting at 2 mg/kg/day in BA infants at two centers in the UK. There was a significant reduction in bilirubin levels at 1 month, which was more obvious in those who had portoenterostomy before the age of 70 days, but there was no significant effect on clearance of jaundice at 6 months (47% vs 49%) between steroids and placebo or subsequent native liver survival.
They published a follow-up study in 2013, including 44 additional patients treated with high-dose prednisolone starting at 5 mg/kg/day, and found that there was a significant difference in jaundice clearance between both the lowdose and high-dose corticosteroid groups and the placebo group (52% vs 66%, P = 0.037). However, there was no significant improvement in native liver survival (56% vs 48%) when comparing the high-dose group to placebo.
The North American Steroids in BA Randomized Trial (START) reported that there was a nonsignificant improvement in jaundice clearance at 6 months after hepatoportoenterostomy between both steroid groups and a placebo group (59% vs 49%), which was higher in the subgroup undergoing portoenterostomy at less than 70 days (72% vs 57%).
The START trial reported serious adverse events and did not find an overall difference in the number of events in the steroid compared with the control group but did find that adverse events occurred earlier.
The Japanese Biliary Atresia Society conducted a multicenter randomized trial comparing high-dose and low-dose corticosteroid administration and found that bilirubin was significantly lower in the high-dose group at both 1 and 2 months postoperatively, although long-term outcomes were not reported.
At Juntendo, we have not experienced significant adverse effects from corticosteroid administration, which is supported by Davenport’s report.128
ANTIBIOTICS
Intravenous administration of double-agent broadspectrum antibiotics (usually a cephalosporin and an aminoglycoside) is commenced at the start of the operation and continued postoperatively until the C-reactive protein (CRP) is less than 0.3 mg/dL or leukocytosis has resolved.
Oral antibiotics may be administered prophylactically according to the surgeon’s preference in the absence of cholangitis.
CHOLAGOGUES
Ursocholic or aminoethylsulfuric should be started at day 5 postop.
In general, the authors continue intravenous fluids and nasogastric aspiration until bowel activity can be confirmed, usually 3–4 days postoperatively.
Careful monitoring of blood glucose levels, electrolytes, and coagulation is important in the early postoperative period.
Blood tests, including complete blood count, LFTs, and cholinesterase, are assessed routinely for the first 7 days postoperatively and then as required.
Liver biochemistry (including bilirubin) may well worsen in the first postoperative week, whatever the eventual outcome, and should not been seen as discouraging.
At Juntendo, our standard postoperative protocol includes administration of both cholagogues and corticosteroids. An intravenous cholagogue (usually dehydrocholic acid) is commenced on day 2 after portoenterostomy and continued until jaundice clearance is confirmed (total bilirubin ≤1.5 mg/dL).
Oral cholagogues such as ursodeoxycholic acid or aminoethylsulfonic acid are administered once oral feeding is commenced, generally on day 5 after operation and continued thereafter.
Once the CRP falls below 1.0 mg/dL, a decreasing dose regimen of prednisolone is begin intravenously.
The starting dose is 4 mg/ kg/day administered for 3 days, followed by 3, 2, 1, and 0.5 mg/kg/day each for 3 days.
This 15-day cycle can be repeated up to four or five times if there is evidence of clinical benefit such as a decrease in total bilirubin or darkening of stools.
By about the fourth postoperative week, there should be a definite fall in bilirubin and consistently pigmented stools in those who will do well.
During the 4 weeks after portoenterostomy, daily monitoring of stool color and CRP is important, because if pigmented stools become pale or CRP increases, the antibiotic regimen may need to be revised.
Preventing inflammation at the portoenterostomy site during the first 4 weeks after portoenterostomy is crucial to enable bilioenteric fistulae to develop.
Strict attention to nutritional needs is important, and all postoperative cases require fat-soluble vitamin supplementation that may need to be aggressive in some cases, especially with regard to vitamin K.
Medium-chain triglyceride formula milk is advocated to maximize calorie input and facilitate lipid absorption, as medium-chain triglyceride formula milk is processed by the portal vein and is readily available as a source of cellular energy.
An important feature of the authors’ protocol is that if stools begin to turn pale, the corticosteroid cycle is either recommenced from the beginning or the previous dose is readministered, depending on clinical circumstances. The antibiotic regimen is also usually revised.
Should jaundice persist (total bilirubin >1.5 mg/dL) without evidence of apparent clinical benefit, only three cycles of corticosteroids are administered and the patient is actively considered for liver transplantation.
How is postoperative cholangitis managed post-KPE?
CHOLANGITIS
Postoperative cholangitis is a serious setback, can occur in the early postoperative period, especially before bilioenteric fistulae have developed, and should not be undertreated.
It is defined as an elevated serum bilirubin (>2.5 mg/ dL), leukocytosis, and a change from normal to acholic stools in a febrile patient (>38.5°C).
It must be treated by intravenous antibiotics immediately, according to each center’s protocol.
Once resolved, prophylactic antibiotics such as trimethoprim-sulfamethoxazole should be administered orally.
Cholangitis is the most common complication after hepatic portoenterostomy and occurs during the first 2 years in approximately 40% of infants.
Patients with cholangitis present initially with fever, decreased quantity and quality of bile excretion, elevation in serum bilirubin, and signs of infection.
Prompt treatment is necessary to prevent liver damage because recurring attacks cause progressive liver damage.
After initial blood cultures, broad-spectrum antibiotics with good Gram-negative coverage should be commenced and improvement should be rapid.
If stools remain acholic or revert to acholic, a pulse of corticosteroids should be trialed.
It is important to note that cholangitis also may be late-onset and precipitate liver failure, necessitating emergency liver transplantation. Late-onset cholangitis can be fatal, even in long-term survivors, which is of particular concern in Japan where the availability of cadaveric donors is limited. Moreover, living donors (parents of siblings) may be inappropriate because of advanced age or poor health.
Cholestasis is the main risk factor for cholangitis because ducts in patients with BA are very small, and all conduits should be considered to have become colonized by potentially pathogenic biota within a month of surgery.
To decrease the risk for cholangitis, Roux-en-Y biliary reconstruction has been modified by various maneuvers, including lengthening the Roux-en-Y limb from 50–70 cm, total diversion of the biliary conduit, creation of an intestinal valve, and the use of a physiologic intestinal valve.
The antireflux intussusception valve is probably the best modification likely to result in a reduced rate of cholangitis.
A gallbladder conduit is not recommended when the lumen of the patent duct is narrow or when pancreaticobiliary anomalies are demonstrated on cholangiography. Stomas should be avoided to prevent complicating liver transplantation, which may be required later.
Prophylactic long-term oral antibiotics have been advocated to reduce the recurrence of cholangitis, but evidence for their efficacy remains scant with only one randomized controlled trial in a much younger age group.
How is portal hypertension managed post-KPE?
PORTAL HYPERTENSION
Portal hypertension is common after portoenterostomy, even in infants with good bile flow.
One report described 44 of 63 (70%) long-term survivors showing clinical, ultrasonographic, or endoscopic signs of portal hypertension (i.e., splenomegaly).
The basic inflammatory process affecting the extrahepatic ducts in BA also damages the intrahepatic branches, and evidence of persistent hepatic fibrosis has been found in some children despite successful portoenterostomy.
Clinical manifestations of portal hypertension include esophageal varices, hypersplenism, and ascites.
Over time, the susceptibility to complications from portal hypertension seems to decrease, resulting in reduced frequency and severity of variceal bleeding. This observation is difficult to explain and may be related to improvement in hepatic histology or the development of spontaneous portosystemic shunts.
The development of portal hypertension justifies a nonsurgical approach as long as hepatic function is preserved (i.e., the patient remains anicteric with no coagulopathy and normal serum albumin level).
However, in the presence of poor hepatic function, complications from portal hypertension are an indication for liver transplantation.
How is hepatopulmonary syndrome managed post-KPE?
HEPATOPULMONARY SYNDROME AND PORTOPULMONARY HYPERTENSION
Hepatopulmonary syndrome is characterized by cyanosis, dyspnea on exertion, hypoxia, and finger clubbing.
Diffuse intrapulmonary shunting can occur as a complication of chronic liver disease in children with BA as a result of vasoactive compounds from the mesenteric circulation not being able to be deactivated by the liver.
It appears to be more prevalent in children with syndromic BA.
The diagnosis is confirmed by comparing arterial blood gas data taken during inspiration of room air and supplemental oxygen, radionuclide lung scans with macroaggregated albumin to quantify the degree of shunting, and contrast bubble echocardiography.
This complication is progressive and can usually be reversed by liver transplantation.
Portopulmonary hypertension is an uncommon complication, but can develop in long-term survivors after portoenterostomy.
If hepatopulmonary syndrome or portopulmonary hypertension are suspected and therapy is considered necessary, liver transplantation should be encouraged before symptoms worsen, which may prevent the option of transplantation.
How are intrahepatic biliary cysts managed post-KPE?
INTRAHEPATIC BILE LAKE CYSTS
Biliary cysts, or “lakes,” can develop within the livers of shortto long-term survivors at any time after portoenterostomy and cause recurring attacks of cholangitis.
After percutaneous drainage of a bile lake, patients are usually anicteric and the lake cyst may disappear.
Prolonged antibiotics and ursodeoxycholic acid may be helpful in preventing cholangitis, but persistent refractory infection is an indication for liver transplantation.
How are malignant changes managed post-KPE?
HEPATIC MALIGNANCY
Rarely, malignant changes (hepatocellular carcinoma or cholangiocarcinoma) complicate long-standing biliary cirrhosis after portoenterostomy.
A case of hepatocellular carcinoma has been reported in a 19-year-old post–Kasai procedure male BA patient, indicating the need for a high index of suspicion for the development of carcinoma, even in young patients.
What are other metabolic complications post-portoenterostomy?
OTHER COMPLICATIONS
Due to the presence of residual hepatic disease, metabolic problems associated with malabsorption of fat, protein, vitamins, and trace minerals can occur postoperatively because of impairment of bile flow to the gut.
Weight gain after portoenterostomy may be retarded if hepatic dysfunction persists. Essential fatty acid deficiencies and rickets can occur.
Long-term monitoring of growth and development and adequate nutritional supplementation are recommended.
Ectopic intestinal variceal bleeding and pulmonary arteriovenous fistulae are sometimes seen in long-term survivors with chronically impaired liver function.
As more postoperative BA patients are now reaching adulthood, the issue of pregnancy in females is becoming more relevant.
In postsurgical nontransplanted BA patients, preterm cesarean delivery at around 34 weeks’ gestation appears to be reasonable because poor hepatic reserve defines the pregnancy as being high risk.
Conversely, delivery at full term may be possible for selected mothers with good liver function.
What are the differences between a Modified Kasai portoenterostomy, Kasai’s original portoenterostomy, and and Extended portoenterostomy?
(A) Modified Kasai portoenterostomy:
Interrupted shallow sutures (thin broken lines) are placed in the liver parenchyma around the transected biliary remnant, except at the 2 and 10 o’clock positions, where the right and left bile ducts should be.
If sutures are necessary at the 2 and 10 o’clock positions to prevent an anastomotic leak, shallow interrupted sutures (thin dotted lines) are placed only in the connective tissue near the right and left hepatic arteries or the hepatoduodenal ligament at the porta hepatis.
(B) Kasai’s original portoenterostomy.
A continuous suture (looped line) is placed in the side of the transected biliary remnant, except at the 2 and 10 o’clock positions, where sutures (dotted lines) are placed in the connective tissue.
(C) Extended portoenterostomy:
Deep interrupted sutures (bold broken lines) are placed in the liver parenchyma, even at the 2 and 10 o’clock positions.
A mother presents with her icteric, 3-week-old daughter to the emergency department. She is exclusively breastfeeding her daughter who has an adequate amount of wet diapers and stool daily. Biliary atresia is suspected, and a serum sample for total and direct bilirubin is obtained. Which of the following statements is false regarding biliary atresia?
Choices:
1. Biliary atresia is the most common cause of conjugated hyperbilirubinemia in the newborn
2. The “triangular cord” sign is suggestive of biliary atresia
3. The presence of bile pigments in stools rules out biliary atresia
4. Patients have a favorable outcome if the Kasai procedure is performed before 2 months of age
Answer: 3 - The presence of bile pigments in stools rules out biliary atresia
Explanations:
• Biliary atresia is the most common cause of conjugated hyperbilirubinemia is neonates in developed countries, accounting for 20% to 30% of cases. The patient typically presents between 2 to 4 weeks of life with acholic stools and dark urine. The presence of bile pigments in the stools, however, does not rule out biliary atresia, especially in the initial stages. In biliary atresia, there is the involvement of both intra- and extrahepatic bile ducts.
• In conjugated hyperbilirubinemia, the direct portion of total bilirubin is more than 20% of the total bilirubin when total bilirubin is more than 5 mg/dL. Conjugated neonatal hyperbilirubinemia is always pathologic, and further evaluation is warranted to identify the underlying condition.
• The initial imaging study in a newborn suspected to have biliary atresia is abdominal ultrasonography, which will classically show an absent gallbladder and the “triangular cord” sign. The presence of a gallbladder does not rule out biliary atresia, as it may be atretic.
The next step is a percutaneous liver biopsy, followed by an intra-operative cholangiogram. The Kasai procedure (hepatoportoenterostomy) reestablishes bile flow, and the outcome is best when performed before 8 weeks of life.
• Biliary atresia may occur in isolation or be part of a syndrome known as the biliary atresia splenic malformation syndrome. This syndrome is characterized by polysplenia or asplenia associated with other malformations such as situs inversus, malrotation of in-testines, interrupted inferior vena cava and portal vein, and hepatic artery anomalies.
StatPearls
A 3-week-old infant is being evaluated in the neonatal intensive care unit for jaundice. Physical examination reveals a soft systolic murmur with radiation to the axilla. Lab work shows direct hyperbilirubinemia at 0.6 mg/dL, and chest x-ray demonstrates a T11 butterfly vertebra. Which of the following is the most likely underlying hepatic etiology for this patient’s presentation?
Choices:
1. Hepatic vein occlusion
2. Cytomegalovirus infection of the liver
3. Polycystic liver disease
4. Paucity of intrahepatic bile ducts
Answer: 4 - Paucity of intrahepatic bile ducts
Explanations:
• The infant has jaundice due to cholestasis. The physical examination reveals a heart murmur that is consistent with peripheral pulmonic stenosis. This is the most frequent cardiac condition found in patients with Alagille syndrome (ALGS).
The finding of a butterfly vertebra on chest x-ray is the third major clinical feature guiding towards the diagnosis of ALGS.
• Patients with hepatic vein occlusion and congenital cytomegalovirus can present with signs and symptoms of cholestasis; however, associated cardiac conditions or skeletal abnormalities are not commonly seen with this condition.
•The diagnosis of ALGS can be challenging due to the variability of clinical manifestations ranging from no symptoms to life-threatening, even among individuals from the same family that share the same mutation. Most patients present with jaundice or cardiac-related symptoms. Stenosis and congenital paucity of intrahepatic bile ducts represent the underlying etiology for jaundice in this patient.
StatPearls
What are the expected histopathologic findings for biliary atresia?
The entire extrahepatic biliary tree or any segment of it may be involved by the destructive fibroinflammatory process.
The inflammation is typically most active at the porta hepatis with continuous fibrous obliteration of the distal biliary system.
The resected biliary tree is classified histologically into three types.
Type 1 shows absence of bile duct lumen and replacement by a fibroinflammatory cord or tract.
Type 2 shows multiple small lumens less than 50 µm surrounding a fibroinflammatory cord or tract.
Type 3 shows a distorted, large-sized bile duct lumen surrounded by inflammation and fibrosis.
Different histologic types may be seen in a single specimen, such as shown in Figure 43.5 in this patient. Multiple studies failed to correlate the diameter (or the sum of the diameters) of the bile duct remnant with the outcome of the Kasai procedure.
The liver biopsy evaluates the extent of liver injury which is graded on a scale of 1 (portal tract expansion with ductular proliferation) to 4 (cirrhosis).
Bile stasis, intrahepatic bile duct loss, giant cell transformation (so-called giant cell hepatitis), and portal fibrosis are usually found, as shown in Figure 43.6.
In addition, the liver biopsy shows the hallmark features of BA, namely portal expansion with ductular proliferation and presence of bile “plugs” in the bile ducts.
Sherif
A biliary atresia patient, 2 months post-Kasai, is brought by his parents to the emergency room after falling from a low sofa with pain and swelling in the left leg. Extremity films are shown in Figure 43.7. An emergency room resident is surprised at this finding and believes the story is inconsistent with the findings.
Do you agree?
No. Long bone fractures are quite common in patients with BA, occurring in 10%–30% of patients. They are believed to be due to vitamin D deficiency. They can occur with relatively minor trauma and are a common source of morbidity in these patients.
Sherif
What is the most common type of biliary atresia?
BA is a sclerosing cholangiopathy that represents the most common cause of end-stage liver disease and the most common indication for liver transplantation in children.
It occurs in 1:15,000–20,000 in Caucasian populations and has a much higher incidence, approximately double, in Asian populations.
It is an isolated disease of term infants in 85% of cases.
In the remainder of affected patients, it occurs as part of a syndrome, the most common of which is BASM (biliary atresia, splenic malformation [asplenia or polysplenia], and malrotation).
The etiology of BA is multifactorial, but the end result is bile duct epithelial injury that initiates a trajectory of cholestasis, fibrosis, cirrhosis, portal hypertension, and death, if untreated.
An association has been found between cytomegalovirus (CMV) infection and BA, and CMV-positive status has been associated with worse outcomes.
The most common variant, found in up to 90% of cases, is type III, where complete obliteration of the extrahepatic biliary ducts is seen.
Type I BA involves atresia of the distal common bile duct. This type has traditionally been referred to as correctable BA.
Type II, the least common (less than 5%), constitutes atresia of the common hepatic duct with an intact distal biliary tree.
A cystic form can also be seen and is often diagnosed prenatally. It is associated with better outcomes.
Sherif
How do you differentiate Alagille Syndrome from biliary atresia?
Alagille Syndrome is a mimicker of BA.
The underlying pathology is a paucity of bile ducts.
Peripheral pulmonic stenosis is a hallmark of the syndrome.
Vertebral anomalies (butterfly vertebrae) and anterior chamber ocular malformations are also seen.
The histology of Alagille Syndrome is one of bile duct hypoplasia, rather than bile duct proliferation as seen in BA. However, bile duct proliferation may be seen early in Alagille Syndrome. Therefore, a liver biopsy may not always differentiate the two.
A cholangiogram however, would definitively show bile duct patency in Alagille Syndrome. The diagnosis is often suggested early by the presence of associated anomalies.
Currently, Alagille Syndrome can be confirmed on genetic testing by identifying the presence of the JAG-1 gene. This gene mutation is present in 97% of cases.
Sherif
What are contraindications to portoenterostomy for biliary atresia?
Operation before 70 days of age is optimal. Although there are no absolute contraindications to portoenterostomy, the onset of liver failure and portal hypertension is accelerated after 90 days of age. These are seen as relative contraindications.
Some have advocated liver transplantation as primary therapy for such late-presenting patients, but other series have shown reasonable success rates in this population.
In addition to age, other factors associated with a potentially worse prognosis include CMV-positive status, BASM syndrome, the presence of ascites and nodular liver at the time of surgery, and a higher aspartate aminotransferase-to-platelet ratio index (APRi) at time of intervention.
Sherif
How is surgery done for suspected biliary atresia?
The operation starts with a small right upper quadrant oblique incision to identify a potential gallbladder.
If a normal gallbladder is seen containing colored bile, a cholangiogram is performed through a cholecystotomy. Flow into the duodenum excludes BA.
Visualization of a diminutive, but patent, biliary tree is highly suggestive of Alagille Syndrome.
Inspissated bile may also be identified and is suggestive of cystic fibrosis. It can typically be irrigated to resolve the obstruction.
If BA is excluded, a liver biopsy should be performed, if not already done, and the operation terminated.
The presence of an atretic gallbladder, often lacking a true lumen, confirms BA. In that case, the incision should be enlarged and Kasai portoenterostomy should be performed.
Although several modifications to Kasai’s original description have been proposed, the major components of the procedure remain, namely:
- Evisceration of the liver out of the abdomen after division of all suspensory ligaments.
- Exposure of the Rex fossa on the left and division of the bridging hepatic parenchyma.
- Transection of the portal plate flush with the liver capsule at the level of the portal vein bifurcation.
- Creation of a retrocolic 40-cm Roux-en-Y limb with a side to side portoenteric anastomosis.
It is advisable to leave an antiadhesive membrane in the abdomen following the procedure. This may facilitate future dissection if a liver transplant is required.
Laparoscopic portoenterostomy has been reported. However, a moratorium was placed on the minimally invasive procedure, when early outcomes were found to be clearly inferior to the open operation. Despite this, single-institution series of laparoscopic Kasai continue to emerge, demonstrating reasonable outcomes.
Portoenterostomy revision is rarely indicated and should be considered only in patients in whom bile drainage suddenly stops after initial success.
Most pediatric surgeons do not perform the Kasai portoenterostomy frequently. There is emerging evidence from European countries that centralization of initial care and surgery for BA improve outcomes.
Sherif
How is postoperative care done post-Kasai PE?
Intravenous antibiotics should be continued for at least 1 week after operation and switched to prophylactic oral trimethoprim-sulfamethoxazole afterward.
The role of postoperative steroids following the Kasai operation has remained controversial. A randomized controlled trial showed no statistically significant improvement in jaundice clearance, but many believe the benefits in younger patients enrolled in that trial were clinically significant. Several high volume centers continue to use postoperative steroids routinely after portoenterostomy.
Following a successful Kasai operation, pigmented stool is usually seen within 2–3 weeks. A normal conjugated bilirubin level 3 months after surgery predicts long-term success. Such success is typically seen in one-half to two-thirds of patients, but is maintained into adulthood in only half of the patients with initial jaundice clearance.
Therefore, liver transplantation will be required for approximately two-thirds of patients at some point in their life.
Cholangitis is the most common sequel after the Kasai operation and occurs despite antibiotic prophylaxis. In addition to laboratory testing, an ultrasound is typically done to assess for any changes, such as intrahepatic bile duct dilatation, fluid around the porta hepatis, or new liver lesions such as cysts or abscesses. These may indicate a problem with a previously functioning Kasai. The patient should be admitted. Blood cultures should be sent and broad-spectrum antibiotics should be started immediately. The patient should be adequately hydrated. Hemodynamics and urine output should be monitored. Daily bilirubin and liver function tests should be checked. A complete blood count should be checked periodically during the hospitalization.
Small bile duct lakes seen on ultrasound early after surgery may resolve spontaneously. A persistent lake resulting in recurrent infections, as seen in the index case, should be treated by resection or internal drainage.
In addition to prophylactic antibiotics, fat-soluble vitamin levels should be followed carefully in BA patients and supplemented as needed. Some gastroenterologists also place these patients on the choleretic agent ursodeoxycholic acid for an extended duration.
Much research is currently being undertaken regarding the genetics of BA. This may help us understand the etiology of BA and suggest targeted interventions, at least in some specific BA subtypes. It may also help identify genetic factors that affect the outcome and long-term prognosis of the disease.
Sherif
What percentage of children who underwent successful Kasai’s procedure (hepatoportoenterostomy) will have progressive liver disease that requires liver transplantation before adulthood?
A 50%
B 60%
C 70%
D 80%
E 90%
C
Kasai’s procedure performed in the newborn is successful when bile flow is restored. Nonetheless, these patients still carry a risk of 70% or greater of developing cirrhosis that will require liver transplantation before adulthood.
SPSE 1
Biliary atresia liver histology is mimicked by all of the following diseases except:
A total parental nutrition associated cholestasis
B cystic fibrosis
C Alagille’s syndrome
D choledochal cyst
E hepatocellular carcinoma.
E
The results of liver biopsy are critical in making the diagnosis of biliary atresia. The findings of a liver biopsy in biliary atresia include fibrosis, inflammation, and proliferation.
These findings can also be seen with choledochal cysts, bile duct strictures and stones, total parenteral nutrition-associated cholestasis, alpha-1 antitrypsin deficiency, cystic fibrosis, multiple drug resistant 3 deficiency, North American Indian childhood cirrhosis (cirrhin deficiency) and Alagille’s syndrome.
The diagnosis of biliary atresia relies on multiple aspects of the patient history and examination rather than on a single test to make the diagnosis.
SPSE 1
Which of the following histological features can be seen with biliary atresia?
A inflammatory cell infiltration
B expansion of portal tracts with fibrosis
C bile plugs in portal tracts
D syncytial giant cell formation
E all of the above
E
Liver biopsies taken from a patient with biliary atresia usually show fibrosis, inflammation and proliferation.
The characteristic features include expansion of portal tracts, infiltration of inflammatory cells, and portal tracts with bile plugs.
The expansion of the portal tracts may carry varying degrees of fibrosis which may be predictive of long-term success of the Kasai procedure.
There may also be parenchymal changes such as syncytial giant cell formation, lobular disarray and extramedullary haematopoiesis.
SPSE 1
All of these viral agents has been linked to biliary atresia except:
A cytomegalovirus (CMV)
B reovirus
C rotavirus
D human papilloma virus
E hepatitis virus.
D? E?
There are three main viruses that are associated with biliary atresia.
CMV was reportedly found in 24%–38% of affected patients, while reovirus was seen in 55% of patients.
An even higher percentage, 78%, of patients with both biliary atresia and choledochal cysts had identified reovirus infection.
Although rotavirus has been identified in patients with biliary atresia, this has not been a consistent finding. In addition, mouse models have demonstrated that these viruses can cause inflammatory extra-hepatic biliary obstruction.
other viruses that have been reported with biliary atresia include respiratory syncitial virus, human papilloma virus and Epstein–Barr virus.
Hepatotropic viruses such as hepatitis A, B and C have not been related to biliary atresia.
SPSE 1
Which of the following is considered non-controversial postoperative therapy after a Kasai procedure?
A fat-soluble vitamins
B ursodeoxycholic acid
C steroids
D all of the above
E B and C
A
The preoperative management of patients undergoing Kasai’s procedure includes nutritional supplementation, fat-soluble vitamins and antibiotics.
The postoperative management of patients following a Kasai procedure has brought forth various strategies that have not shown to be statistically beneficial and therefore remain controversial.
The use of steroids is thought to improve bile flow following a Kasai procedure. When steroid use is implemented, the initial doses are given intravenously and then transitioned to oral steroids followed by a taper regimen.
ursodeoxycholic acid is another controversial therapy regimen which follows the administration of intravenous bile acids to also aid in bile flow following a Kasai procedure.
The use of fat-soluble vitamins is a mainstay of both pre- and postoperative management and is not considered controversial.
SPSE 1
Postoperative cholangitis is characterised by which of the following?
A fever
B abnormal liver function tests
C pale stools
D jaundice
E all of the above
E
Cholangitis occurs in about 30%–50% of postoperative patients following a Kasai procedure.
These patients usually present with fever and abnormal liver function tests.
The patient may also develop signs and symptoms characteristic of their presentation prior to the Kasai such as jaundice and acholic stools.
In this clinical scenario patients need to be evaluated for sepsis.
In the case of recurrent cholangitis with resultant liver decompensation, the next treatment step is likely a liver transplant.
SPSE 1
Symptomatic portal hypertension may present with all of the following except:
A variceal bleeding
B ascites
C splenomegaly
D perianal hematoma
E hepatic encephalopathy.
D
Portal hypertension has been documented to occur in almost two-thirds of patients following a Kasai procedure.
The presenting symptoms are oesophageal varices, ascites, and splenomegaly.
Portal hypertension is often accompanied by worsening jaundice and synthetic liver function, which in severe cases can lead to hepatic encephalopathy.
unlike hemorrhoids and anorectal varices, perianal hematoma is not associated with portal hypertension.
SPSE 1
In children diagnosed with biliary atresia, improved outcome is mainly attributed to which of the following?
A early diagnosis
B referral to specialist centres
C steroid use postoperatively
D A and B only
E none of the above
D
Early Kasai and a multidisciplinary centre have both been shown to improve the success of Kasai’s procedure, survival outcomes and patient quality of life.
Performing Kasai’s procedure within 60 days of life has shown significant benefit in patients and extended the number of years until liver transplantation.
one study performed in France found that if the Kasai was performed before 45 days of life, 29% of children could live with their native liver for longer than 15 years.
In addition, the preoperative and postoperative care of patients diagnosed with biliary atresia is best served by a team of specialists who are familiar with the disease, surgical procedure and postoperative complications.
SPSE 1
The two main causes of cholestatic jaundice in early infancy are:
A idiopathic neonatal hepatitis and biliary atresia
B Gilbert’s disease and biliary atresia
C haemolytic disease and biliary atresia
D haemolytic disease and Gilbert’s disease
E none of the above.
A
The differential diagnosis for jaundice in early infancy is vast and requires a full workup. However, the two main causes of cholestatic jaundice are idiopathic neonatal hepatitis and biliary atresia.
Causes of neonatal cholestatic jaundice can be divided into intrahepatic and extrahepatic causes.
Extrahepatic causes include biliary atresia, choledochal cyst, bile duct stenosis, strictures and cholelithiasis, spontaneous perforation of the common bile duct, and tumours or masses.
Intrahepatic causes are numerous and are generally divided into six possible categories: infectious, metabolic, genetic, toxic, cholangiopathies and others.
Gilbert’s disease is an inherited cause of unconjugated hyperbilirubinaemia. Although it is rare, Gilbert’s disease is the most common genetic cause of unconjugated hyperbilirubinaemia.
Haemolytic anaemia is caused by the destruction of premature erythrocytes and is also characterised by unconjugated hyperbilirubinaemia.
SPSE 1
What is the most reliable method to differentiate idiopathic neonatal hepatitis and biliary atresia?
A magnetic resonance cholangiography (MRCP)
B hepatobiliary scintigraphy (HBS)
C abdominal ultrasound
D liver biopsy
E A and B
D
Radiation-sparing radiological studies are frequently employed in children because they are non-invasive. However, radiological studies cannot reliably differentiate causes of neonatal jaundice especially idiopathic neonatal hepatitis and biliary atresia.
In one study, MRCP was shown to have a 85.29% sensitivity and 57.14% specificity for biliary atresia. HBS was documented to have a 88.24% sensitivity and 45.71% specificity while abdominal ultrasound had a 50% sensitivity and 82.85% specificity.
Compared with liver biopsy (100% sensitivity, 94.29% specificity), these imaging modalities are less useful in making the diagnosis of biliary atresia.
SPSE 1
Biliary atresia is an obliterative cholangiopathy characterised by which of the following?
A It can affect neonates and adults.
B It should be treated primarily by liver transplant.
C It always eventually requires transplant.
D It can be effectively treated by the Kasai procedure.
E It always involves obliteration of the extrahepatic bile duct.
D
Biliary atresia is an obliterative cholangiopathy that affects neonates. There is no similar process in adults.
liver transplant is reserved for those patients that deteriorate after primary therapy with Kasai’s procedure.
Some patients do well in the long term with only a Kasai and do not go on to need a liver transplant.
Biliary atresia most commonly affects the extrahepatic bile ducts, but can occur in the intrahepatic bile ducts without affecting the extrahepatic duct.
SPSE 1
Which lab value is not helpful in making the diagnosis of biliary atresia?
A elevated gamma-glutamyl transpeptidase (GGT)
B elevated aspartate transaminase (AST)
C decreased alanine transaminase (ALT)
D decreased albumin
E increased alkaline phosphatase
D? C?
Biliary atresia is associated with an increase in AST, ALT, conjugated bilirubin, total bilirubin and GGT.
It is also associated with malnutrition and a decrease an albumin.
SPSE 1
Which of the following presentations is not consistent with biliary atresia?
A A 22-day-old ex-34-weeker presents with jaundice, acholic stools, splenomegaly and indirect hyperbilirubinaemia.
B A 15-day-old term male with jaundice and an elevated gammaglutamyl transferase.
C A 4-month-old term female with jaundice, tea-coloured urine, ascites and hepatomegaly.
D A 20-day-old ex-34-weeker presents with jaundice and a normal liver biopsy.
E A 1-month-old female term baby presents with acholic stools and a triangular cord sign on ultrasound.
A
The clinical presentation of biliary atresia is characterised by jaundice, acholic stools, splenomegaly in relationship to portal hypertension but not indirect hyperbilirubinaemia.
There is no conjugation defect of bilirubin in biliary atresia and thus these patients have direct hyperbilirubinaemia.
The most common abnormal liver function test in biliary atresia is an elevated gamma-glutamyl transferase.
Patients who are diagnosed with biliary atresia late may present with ascites in addition to jaundice and tea-coloured urine.
liver biopsies taken before 6 weeks can sometimes lack the typical features of biliary atresia.
The triangular cord sign or a hyperechogenic liver hilum on ultrasound is a specific finding for biliary atresia in most cases. It is, however, operator dependent and has varying sensitivity.
SPSE 1
Post-surgical conditions associated with biliary atresia after Kasai’s procedure include:
A cholangitis, steatorrhoea, cholecystitis, biloma, afferent- loop syndrome
B cholangitis, steatorrhoea, cholecystitis, biloma, sepsis
C portal hypertension, cholangitis, afferent-loop syndrome, bile lake infection
D afferent-loop syndrome, cholangitis, choledochal cyst, cholecystitis
E cholangitis, steatorrhoea, oesophageal varices, dumping syndrome.
C
Kasai’s procedure is largely palliative with the vast majority of patients going on to have progression of their disease including worsening progressive liver disease, portal hypertension, oesophageal varices and continued steatorrhoea.
Because the procedure directly connects the intestine to the biliary tree, recurrent cholangitis, bile lake infection and biliary sepsis are persistent postoperative risks.
Biloma and afferent-loop syndromes can occur from technical complications at the portoenterostomy site.
Cholecystitis, choledochal cyst and dumping syndrome are not associated with Kasai’s procedure.
SPSE 1
Which of the following factors has not been shown to have prognostic value in determining the success of Kasai’s procedure?
A surgeon experience
B presence of cirrhosis
C age of patient at the time of procedure
D biliary diversion
E polysplenia
D
Biliary diversion has not been shown to have prognostic value in determining the success of Kasai’s procedure.
Improved outcomes are associated with increased surgeon experience and decreased patient age at the time of Kasai.
Worse outcomes are associated with polysplenia and the presence of cirrhosis at the time of Kasai.
SPSE 1
In a case of diagnosed biliary atresia, what is the optimal timing of Kasai procedure?
A before 60 days of life
B before 50 days of life
C as soon as possible
D before 40 days of life
E none of the above
C
Although timing is still controversial, the largest series of patients demonstrates that outcomes are improved the earlier a Kasai is performed.
Thus the procedure should be performed as soon as possible after diagnosis.
SPSE 1
Which of the following is an indication for liver transplant after a successful Kasai procedure?
A refractory variceal bleeding
B elevated total bilirubin
C polysplenia
D recurrent cholangitis
E all of the above
A
Refractory variceal bleeding is an indication of severe portal hypertension and cirrhosis.
It is an indication to proceed to liver transplant.
An elevated bilirubin, in and of itself, is not an indication for liver transplant.
Polysplenia is associated with worse outcomes after Kasai but is not, by itself, an indication for liver transplant.
Cholangitis in itself is not an indication for liver transplantation, and can be managed conservatively with antibiotics.
SPSE 1
At what age is liver transplant usually indicated for infants in whom the Kasai procedure is not technically successful and biliary drainage does not occur?
A immediately
B 2–4 years
C 6 months to 2 years
D 9 months to 1.5 years
E none of the above
C
The typical age of transplant in patients who have undergone a technically unsuccessful Kasai procedure is 6 months to 2 years.
SPSE 1
Which molecular marker has been shown to have a relationship with progression of disease after successful Kasai?
A osteopontin
B basic fibroblast growth factor
C hepatocyte growth factor
D transforming growth factor-β
E all of the above
E
osteopontin, basic fibroblast growth factor and hepatocyte growth factor are associated with biliary atresia progression.
A raised level of transforming growth factor-β is associated with improved biliary atresia outcomes.
SPSE 1
Regarding type and classification of biliary atresia, which of the following is false?
A. Type I atresia at porta is the most common.
B. Type I is the obliteration of the common bile duct, while the proximal bile ducts are patent.
C. Type IIa is atresia of the hepatic duct, with cystic bile ducts found at the porta hepatis.
D. Type IIb is atresia of the cystic duct, common bile duct, and hepatic ducts.
E. Type III is involvement of the extrahepatic biliary tree and intrahepatic ducts of the porta hepatis.
A
Type III atresia at portahepatis is the most common, about 88 percent.
Syed/MCQ
Regarding cause of biliary atresia, which is true?
A. True cause is still unknown.
B. Failure of extrahepatic and intrahepatic duct system to meet.
C. Environmental factors.
D. Viral infection.
E. All of the above.
E
A, B, C, and D are all true. In addition to these other theories indicates that loss of blood supply, abnormal bile acid, metabolism and pancreaticobiliary maljunction.
Syed/MCQ
Regarding presentation of biliary atresia, which is true?
A. Most infants are preterm.
B. Classical triad is abdominal pain, abdominal mass, and jaundice.
C. The earlier the presentation, the better the prognosis.
D. The child never presents with hepatic decompensation.
E. Clear urine and dark stool are commonly seen.
C
Earlier the presentation, better the prognosis. Abdominal pain, abdominal mass, and jaundice are the triad seen in choledochal cyst. Jaundice, claycolour stool, and hepatomegaly are the triad seen in biliary atresia. Child may presents with hepatic decompensation, oesophagal variceal bleeding and infection.
Syed/MCQ
In preoperative management of biliary atresia, what is not required?
A. Choleretics.
B. Antibiotic.
C. Upper GIT contrast study.
D. Metabolic and nutritional care.
E. Essential fatty acid supplement.
C
Upper GIT contrast study is generally not required.
Syed/MCQ
All are true regarding surgical technique in biliary atresia except:
A. Roux-en-Y with intussuscepted valve reduces the chances of cholangitis.
B. Modification by shortening the loop of Roux-en-Y reduces the chances of cholangitis.
C. Roux-en-Y is the operation for non-correctable type.
D. Roux-en-Y is the operation for correctable type.
E. Modification by Kasai’s procedure is for prevention of cholangitis
B
Modification by prolonging the loop of Roux-en-Y reduces the incidence of cholangitis.
Syed/MCQ
Select the best answer about the causes/cause of cholangitis after surgery for biliary atresia.
A. Portal venous infection.
B. destruction of lymphatics at porta hepatitis.
C. bacterial translocation.
D. all of the above.
E. none of the above.
D All of the above.
Syed/MCq
Regarding complications of surgery for biliary atresia, which of the following statements is false?
A. Cholangitis.
B. Portal hypotension.
C. Stricture of anastomosis.
D. Leakage of anastomosis and peritonitis.
E. None of the above.
E A, B, C and D all statements are true.
Syed/MCQ
The best answer among following regarding differential diagnosis of biliary atresia is:
A. Biliary hypoplasia.
B. Choledochal cyst.
C. Inspissated bile syndrome.
D. Neonatal jaundice.
E. All of the above.
E
Differential diagnosis also includes neonatal hepatitis, acquired obstruction like external pressure or stone, glycogen storage disease, lysosomal storage disease, G6PD deficiency and hemolytic disease.
Syed/MCQ
Regarding management of biliary atresia, which of the following is false?
A. Pre-operative presence of gallbladder is an indication of cholangiography.
B. Preoperative gallbladder is used as guide.
C. In Roux-en-Y portoenterostomy, a 20 cm Roux-en-Y loop, 10 cm distal to duodenojejunal junction is used.
D. Pre-operative biopsy is taken from right lobe.
E. If biopsy shows ductules >150 micro-m, this indicates a good prognosis.
C
20 cm loop is too short; about 40 cm loop of jejunum is used.
Syed/MCQ
Regarding complication and survival of biliary atresia, which of the following is false?
A. Hepatic fibrosis stops once achievement of good biliary drainage.
B. Early cholangitis after portoenterostomy is noted in more than 20 percent of cases.
C. Portal hypertension is seen in more than 50 percent of cases.
D. Survival after liver transplantation is better than surgery for biliary atresia.
E. There is relationship between the age at which portoenterostomy is performed and restoration of bile flow.
A
Hepatic fibrosis may increases even after achievement of good biliary drainage in 70 percent of cases.
After portoenterostomy, early cholangitis is noted in 3–60 percent of cases.
Portal hypertension has been seen in about 68 percent of cases.
Post-surgical 5-year survival is 32 percent, and with liver transplantation about 70 percent.
The relationship between time at which portoenterostomy is performed and restoration of bile flow is less than 10 weeks 65 per cent and more than 10 weeks 25 percent.
Syed/MCQ
After portoenterostomy for biliary atresia, which one of the following statements is false?
A. Most patients require liver transplantation within three years.
B. The patients who survive following Kasai portoenterostomy remain free of jaundice for 5–10 years.
C. Portoenterostomy provides long-term biliary drainage in about onethird of patients.
D. Cholangitis is the most common complication.
E. Age of the patient is the most common predictor of long-term outcome.
A
Most patients require liver transplantation within 6 months.
Syed/MCQ
Ultrasound finding of biliary atresia is:
A. Doughnut sign.
B. Triangular cord sign.
C. Sandwich sign.
D. None of the above.
E. All of the above.
B
Triangular cord sign.
Syed/MCQ
