Biliary Atresia

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Diagnosis and reasoning

This infant has presented with prolonged jaundice - a very common clinical scenario. In the vast majority of these patients, the jaundice is physiological in origin (due to causes such as breast milk jaundice). However, note that physiological jaundice typically manifests around 3 to 5 days following birth and usually disappears by 2 weeks of age. Physiological jaundice at 5 weeks of age would be somewhat unusual - thus she requires further evaluation. While the history of normal appetite and growth initially appears reassuring, examination reveals an alarming finding : hepatosplenomegaly. This is highly suggestive of cholestatic jaundice, with the most likely etiologies being bile duct abnormalities (such as biliary atresia or a choledochal cyst), infections (such as neonatal hepatitis) and metabolic or storage disorders (such as galactosemia or Woolman disease). Note that infants with neonatal infections or metabolic diseases tend to be ill. This is as opposed to patients with bile duct abnormalities, who may initially appear healthy. The first investigation in these patients should be estimation of the serum bilirubin fractions. This patient shows a markedly high total bilirubin with a dominant direct fraction - i.e. direct hyperbilirubinemia (conjugated hyperbilirubinemia). This confirms the presence of hepatic cholestasis. As bile duct abnormalities are the most likely diagnosis, a suitable follow up investigation would be a fasting ultrasound scan of the abdomen, which is safe and non-invasive. In this patient, ultrasonography shows an atretic, thin gallbladder - indicating a poor supply of bile. In addition, the increased periportal echogenicity is suggestive of periportal fibrosis. These findings when considered together are suggestive of biliary atresia. Biliary atresia is a potentially lethal condition which requires surgical management - thus definitive confirmation is mandatory. A liver biopsy is sensitive and specific for diagnosis and should be considered at this point. This patient's liver biopsy shows diffuse bile ductular proliferation with bile plugs - indicating large bile duct obstruction. This is sufficient to confirm the diagnosis. She should undergo a Kasai portoenterostomy as soon as possible. Liver transplantation is not indicated immediately. Phototherapy and exchange transfusion are of no benefit.


Discussion

Biliary atresia is the commonest cause of neonatal liver disease, with an incidence of approximately 1 in 10,000 live births. The onset is at birth and the disease is uniformly fatal if left untreated. The initial lesion in biliary atresia is progressive obliteration of the extrahepatic biliary tree. This results in hepatic cholestasis and damage to the intrahepatic bilary tree. The ultimate outcome is hepatic fibrosis terminating in cirrhosis with portal hypertension. The underlying etiology is poorly understood. Suggestions include aberrant early bile duct development, an aberrant immune response, abnormalities of bile acids and perinatal viral infections (such as cytomegalovirus or reovirus). These infants typically present with a history of prolonged neonatal jaundice, which may not necessarily date from birth. In addition, close questioning may reveal a history of dark urine and pale stools - classical symptoms of cholestasis. Examination usually shows an enlarged liver, which is often firm or hard in consistency. Splenomegaly is also common. As portal hypertension sets in, these patients develop ascites and worsening splenomegaly and may also experience bouts of hematemesis (secondary to esophageal varices). Note that these infants often full term babies, and appear well at birth and in the first few weeks of life. The first and most important investigation is fractionation of serum bilirubin levels. Patients with biliary atresia always demonstrate a conjugated hyperbilirubinemia. Note that conjugated hyperbilirubinemia is defined as either an absolute direct bilirubin level > 2 mg/dl, or a direct bilirubin fraction composing > 20% of the total serum bilirubin. Evaluation of the liver and biliary tract should be the next step. Ultrasonography is non-invasive and may demonstrate an absent or atretic gallbladder, absence of dilatation of the biliary tree and periportal fibrosis. The "triangular cord sign" (an echogenic area in the porta hepatis) is highly specific for biliary atresia but is rare. While the overall sensitivity and specific of ultrasound for diagnosis of biliary atresia is low, ultrasound is of benefit in exclude other biliary duct abnormalities, such as a choledochal cyst. Hepatobiliary scintiscanning (HIDA scanning) is an alternative technique of evaluation the biliary tract. The patient is injected with technetium-labelled tracer, which is then tracked as it is taken up by the liver and excreted via the biliary tract into the small intestine. A HIDA scan is almost 100% sensitive, as biliary atresia can be virtually ruled out if the tracer passes into the small bowel. However, the specificity is low, as biliary atresia is just one of many causes of a non-draining scan. Percutaneous liver biopsy has a 90% sensitivity and specificity for diagnosis in the hands of an experienced pathologist. Intraoperative cholangiography is the gold standard for diagnosis and definitively demonstrates the anatomy and degree of patency of the extrahepatic biliary tract. Note that these patients may develop complications of cholestasis such as coagulopathy or the hepatorenal syndrome. Investigation and close monitoring in this regard is mandatory. Surgery is the only definitive therapy, with the current standard of care being the Kasai portoenterostomy (where the porta hepatis is anastomosed to the the small bowel). Most authorities agree that surgery should be performed as soon as possible - delaying intervention for too long may result in irreversible sclerosis of the intrahepatic bile ducts. Of the patients who undergo a Kasai portoenterostomy, roughly one-third survive over 10 years without liver transplantation. In another third, the bile flow remains adequate, but cirrhosis sets in over time. In the remaining third, bile flow is inadequate from the start. Liver transplantation should be considered when these patients manifest symptoms of end stage liver disease (such as growth failure, decreased synthetic function, ascites and portal hypertension and progressive jaundice). Close follow up following surgery is essential, as almost 50% of patients are at risk of developing cholangitis. In the long term, these patients may develop progressive liver failure, and are also at an increased risk for Hepatocellular carcinoma.


Take home messages

  1. A prompt evaluation is indicated for prolonged neonatal jaundice to determine if conjugated hyperbilirubinemia is present.
  2. A high index of suspicion is key to making a diagnosis of biliary atresia.
  3. Once diagnosed, a Kasai portoenterostomy should be performed as early as possible.
  4. Liver transplantation is indicated when symptoms of end stage liver disease occur.

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