Congenital disorders of the liver, biliary tract, and pancreas are rare or very rare.
Biliary atresia is a rare congenital disorder in which some or all of the bile ducts fail to develop or develop abnormally. As a result, bile is unable to drain from the liver (see cholestasis). Unless the atresia can be treated, secondary biliary cirrhosis (a serious liver disorder) will develop and may prove fatal. Symptoms include jaundice, usually beginning a week after birth, and the passing of dark urine and pale faeces. Treatment is by surgery to bypass the ducts. If this fails, or if the jaundice recurs, a liver transplant is required.
In more detail - technical
Biliary atresias present with cholestatic jaundice starting after the first 2 weeks of life and may eventually cause biliary cirrhosis and liver failure. Prognosis depends on the type of atresia: (1) intrahepatic—both nonsyndromic (with cirrhosis usually developing in late childhood, and fatal without liver transplantation) and syndromic (e.g. Alagille’s syndrome, due to mutation in the JAG1 gene, with dysmorphic and other features, and a tendency for recovery of liver function in adolescence), or (2) extrahepatic—which is usually fatal within 6 months of birth unless treated by hepatic portoenterostomy and/or liver transplantation.
Pathogenesis of congenital disorders of the biliary tract
During the 4th week of gestation the liver arises as a bud of cells (the hepatic diverticulum) from the ventral wall of the foregut. At about the 8th week of gestation a layer of liver precursor cells around the portal vein branches differentiate to form a sleeve, termed the ductal plate. This sleeve duplicates to form a double layer of cells which by 12 weeks is remodelled by dilatation of segments of the double-layered ductal plate to form tubules that become the intrahepatic bile ducts. Nontubular parts of the plate disappear and the bile ducts form part of the portal tracts.
Congenital disorders of the biliary tract are classified into two main groups: diseases characterized by inflammatory destruction of the bile ducts (the biliary atresias) and diseases marked by ectasia of the bile ducts with varying degrees of fibrosis (the fibropolycystic diseases). Both of these groups of disorders are related to the persistence or lack of remodeling of the embryonic ductal plate. They are termed ‘ductal plate malformations’.
Ductal plate malformations can be seen on ultrasound or CT scans as a circular lumen containing a fibrovascular cord.
Biliary atresias are classified into extrahepatic biliary atresia and intrahepatic biliary atresia (paucity of intrahepatic bile ducts). Biliary atresia does not represent agenesis of the bile ducts but is the result of progressive bile duct destruction from an inflammatory disease of unknown cause. In extrahepatic biliary atresia the destructive cholangitis affects not only part or the whole of the extrahepatic bile duct but also intrahepatic bile ducts and leads to paucity of intrahepatic bile ducts. In intrahepatic biliary atresia the destructive cholangitis is restricted to the intrahepatic bile ducts. Intrahepatic biliary atresia can be classified further into a nonsyndromatic or a syndromatic type (Alagille’s syndrome or arteriohepatic dysplasia). About one-quarter of patients with extrahepatic biliary atresia have evidence of ductal plate malformation indicating that the destructive cholangitis started early in fetal life.
Symptoms and signs
Biliary atresia presents as cholestatic jaundice starting after the first 2 weeks of life. The infant develops jaundice with pale stools, dark urine, and hepatomegaly. Itching is often prominent. Bile pigments may stain the growing teeth greenish. The jaundice steadily deepens and xanthomas of the palm and knees, rickets, a bleeding tendency, and growth failure may develop. Biliary atresia may eventually cause biliary cirrhosis with pigmentation (due to melanin), portal hypertension, ascites, and liver failure.
The progress of biliary atresia depends on the type. Infants with extrahepatic biliary atresia (usually girls) have a steadily deepening jaundice and biliary cirrhosis soon develops. Untreated, these children usually die by 6 months of age. The fate of infants with intrahepatic biliary atresia depends on whether they have a syndromatic or nonsyndromatic atresia. Children with nonsyndromatic intrahepatic biliary atresia survive longer than those with extrahepatic biliary atresia, but biliary cirrhosis eventually develops in later childhood. In contrast, patients with syndromic intrahepatic biliary atresia (Alagille’s syndrome) tend to recover normal liver function as they become adolescent. Infants with Alagille’s syndrome can be recognized by the associated features, which include a characteristic facies (a flattened and triangular-shaped face), pulmonary stenosis, vertebral abnormalities, and a change in the eyes (embryotoxon). Some patients have growth and mental retardation. Alagille’s syndrome is a dominantly inherited disorder associated with mutations in the Jagged 1 (JAG1) gene. JAG1 encodes a ligand in the Notch intercellular signaling pathway.
Jaundice is common in early infancy. In the early neonatal period jaundice is usually due to haemolysis and impaired bilirubin conjugation. After 2 weeks, jaundice is usually cholestatic. There are many causes of cholestasis in infancy and childhood. The most common are extrahepatic and intrahepatic biliary atresias, neonatal hepatitis (such as hepatitis A, B, and C, rubella, and cytomegalovirus infection), metabolic causes (such as galactosaemia, α1-antitrypsin deficiency, and tyrosinaemia), and the ‘inspissated bile syndrome’ (congenital spherocytosis).
Liver function tests show a cholestatic (biliary obstructive) pattern. Serum bilirubin and alkaline phosphatase levels are markedly raised with only modest elevations of serum transaminases. Later, very high levels of serum cholesterol may develop.
Histological examination of the liver cannot distinguish between intrahepatic and extrahepatic biliary atresia. Liver biopsy shows severe centrizonal cholestasis and a prominent giant-cell reaction. In the portal tracts bile ducts are reduced. Later in the course of the disease the portal tracts are devoid of bile ducts and biliary cirrhosis is present.
The initial step in the management of infants with cholestasis is to differentiate between intrahepatic and extrahepatic biliary atresia. Since the clinical and laboratory findings are similar, this distinction requires imaging techniques. In extrahepatic biliary atresia, scintiscanning with 99Tcm-labelled HIDA (dimethyl acetanilide iminodiacetic acid) shows accumulation of the label in the liver but none enters the biliary tree. Percutaneous and endoscopic cholangiography provides more precise anatomical detail.
Treatment and prognosis
General supportive measures include parenteral administration of fat-soluble vitamins A, D, K, and E. Medium-chain triglycerides as a source of fat, cholestyramine to relieve itching, and ursodeoxycholic acid as a choleretic help some patients.
Extrahepatic biliary atresia
Hepatic portoenterostomy (Kasai’s operation) has been the treatment of choice for extrahepatic biliary atresia and is still widely performed. Approximately 25 to 35% of patients who undergo a Kasai portoenterostomy will survive more than 10 years without liver transplantation. One-third of the patients drain bile but develop complications of cirrhosis and require liver transplantation before the age of 10. For the remaining one-third of patients, bile flow is inadequate following portoenterostomy and the children develop progressive fibrosis and cirrhosis. The portoenterostomy should be done before there is irreversible sclerosis of the intrahepatic bile ducts. Consequently, a prompt evaluation for conjugated hyperbilirubinaemia is indicated for any infant older than 14 days with jaundice.
Intrahepatic biliary atresia
Fibropolycystic disease encompasses a family of rare congenital hepatobiliary diseases that arise due to malformations of the embryonic ductal plate. These diseases include polycystic liver, congenital hepatic fibrosis, congenital intrahepatic biliary dilatation (Caroli’s disease), choledochal cysts, and microhamartomas (von Meyenberg complexes). Many patients will have more than one disease. The combination of congenital hepatic fibrosis and Caroli’s disease is characteristic as these patients develop first variceal haemorrhage (due to congenital hepatic fibrosis) and later recurrent cholangitis (due to Caroli’s disease). Associated kidney defects are common. Malignant change may complicate congenital hepatic fibrosis, Caroli’s disease, choledochal cysts, and microhamartomas. These diseases are of widely differing severity and the prognosis in an individual patient is determined by the fibropolycystic diseases present.
Polycystic liver disease
The infantile type is inherited as an autosomal recessive disease and is usually rapidly fatal due to the associated renal disease. Adult polycystic liver disease is more common and has a dominant inheritance. Two separate genes, PRKCSH and SEC63, have been identified to cause familial adult polycystic liver disease. The patient is usually a woman presenting in the fourth or fifth decade. The liver contains many thin-walled cysts filled with a clear or brownish liquid (due to altered blood). The cysts vary in size from a pinhead to about 10 cm in diameter. The remainder of the liver is normal. Patients present with right upper quadrant pain and increasing girth. Examination reveals an enlarged liver as the cause of the upper abdominal swelling. Liver function tests are normal. Provided no other fibropolycystic diseases are present, polycystic liver disease is benign. Some patients with polycystic liver disease also have polycystic kidneys or nephrocalcinosis. The associated renal disease may cause serious complications including renal failure. The diagnosis can be confirmed by ultrasound or CT scanning, which show numerous thin-walled cysts of low density. The enlarged polycystic liver causes some patients considerable discomfort. It is best treated by percutaneous aspiration of the larger cysts using ultrasound guidance in order to reduce liver size. Percutaneous aspiration treatment can be performed repeatedly.
Congenital hepatic fibrosis
This is a rare autosomal recessive condition which is usually diagnosed before 10 years of age. The main complication is portal hypertension. Children present with a large, very hard liver and splenomegaly or bleeding from oesophageal varices. Congenital hepatic fibrosis may be misdiagnosed as cirrhosis. Liver function tests are normal or only slightly deranged. Ultrasound scans show the liver contains many bright areas due to the dense bands of fibrous tissue. The diagnosis is made by liver biopsy which shows normal liver parenchyma surrounded by fibrous septa containing structures resembling bile ducts.Patients with congenital hepatic fibrosis bleed repeatedly from oesophageal varices, but because liver function is well preserved they do not develop portosystemic encephalopathy. Portocaval shunts will stop the variceal bleeding and are well tolerated. Liver transplantation has also been used successfully.
The long-term prognosis in congenital hepatic fibrosis is usually determined by the associated renal disease. Renal lesions include renal dysplasia, medullary cystic disease, and infantile or adult-type polycystic kidneys. The kidneys are rarely normal and renal failure eventually develops in many patients. However, renal transplants have been successful.
Congenital intrahepatic biliary dilatation (Caroli’s syndrome)
In Caroli’s syndrome the common bile duct is normal but the intrahepatic ducts have bulbous dilatations with normal ducts between. The mode of inheritance is unknown. While the cystic dilatations of the bile ducts remain uninfected the patient is symptom free. Eventually, ascending infection leads to cholangitis, which can be intractable with the formation of gallstones and liver abscesses. Caroli’s syndrome usually presents in early adulthood as cholangitis. Most patients are male. Liver function tests show cholestasis with elevations of serum bilirubin and alkaline phosphatase and modest elevations of the transaminases. The diagnosis is made by endoscopic cholangiography. Magnetic resonance cholangiography (MRC) and CT scans can also demonstrate the syndrome. The natural history of Caroli’s disease is of recurrent cholangitis which is very resistant to antibiotics. Biliary cirrhosis eventually develops. Bile duct cancer develops in about 10% of cases. Treatment is difficult; antibiotics are usually only partially effective, and liver transplantation is compromised by the extensive sepsis.
About one-half of the patients with congenital hepatic fibrosis or Caroli’s disease will also have the other disease. The clinical presentation in these patients is distinctive. As in Caroli’s disease, males predominate. The first complication is variceal haemorrhage followed about 10 years later by recurrent cholangitis.
Microhamartomas (von Meyenberg complexes)
Microhamartomas are groups of rounded biliary channels embedded in a collagen stroma located around portal tracts. The appearances are of localized islands of congenital hepatic fibrosis. Microhamartomas are usually asymptomatic and discovered incidentally on liver biopsy. They may be associated with other fibropolycystic diseases and are a rare cause of portal hypertension. Bile duct and pancreatic cancers are commoner in these patients.
Chardot C, et al. (1999). Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996. Hepatology, 30, 606–11.
Desmet VJ (1992). Congenital diseases of intrahepatic bile ducts: variations on the theme ‘ductal plate malformation’. Hepatology, 16, 1069–83.
Sherlock S, Dooley JS (1997). Diseases of the liver and biliary system, 10th edition. Blackwell Scientific Publications, Oxford.
Sherlock S, Summerfield JA (1991). A colour atlas of liver disease, 2nd edition. Wolfe Medical Publications, London.
Summerfield JA et al. (1986). Hepatobiliary fibropolycystic diseases; a clinical and histological review of 51 patients. J Hepatol, 2, 141–56.