Disorders of the Intra- and Extrahepatic Bile Ducts
Case 9 -
Kay Washington, M.D., Ph.D.
Pathology, C-3321 MCN
Vanderbilt University Medical Center
Nashville, TN 37232-2561
This 59 year old woman developed shaking chills and fever following cholangiogram. After
treatment with antibiotics, she underwent resection of the left lobe of the liver.
On gross examination, cystically dilated bile ducts containing biliary sludge
and stones were present. These dilatations measured up to 2 cm in diameter. Microscopically, periductal
fibrosis surrounds the dilated ducts and smaller interlobular ducts. The dilated ducts contains
inspissated bile intermixed with neutrophils, and there is a sparse inflammatory infiltrate in the
fibrotic wall. The duct epithelium is focally hyperplastic but not dysplastic. The liver immediately
adjacent to the dilated ducts shows bile ductular proliferation, a chronic inflammatory infiltrate in the
portal areas and periductal edema and fibrosis. Changes of congenital hepatic fibrosis are not present.
Click on each slide thumbnail image for an enlarged view:
Involvement of the large intrahepatic bile ducts by the ductal plate malformation process gives rise to congenital dilatation of bile ducts in Caroli's disease. These dilated ducts are predisposed to bile stasis, stone formation, and infection.
Bile Duct Epithelial Hyperplasia in Caroli's Disease
Biliary epithelial hyperplasia may be seen in ducts involved by Caroli's disease. Rarely, frank epithelial dysplasia, which may represent the precursor of cholangiocarcinoma, is seen.
Diagnosis: Caroli's Disease
Cystic diseases of the liver may be broadly divided into the categories of infectious cystic lesions,
which are of course not cysts, as they lack an epithelial lining, and true epithelial cysts. Epithelial
cysts may be further subdivided into mucinous cystic neoplasms, and non-neoplastic cysts. The
non-neoplastic cysts include sporadic simple cysts, which are generally clinically silent and discovered
incidentally. These are typically solitary and are lined by a single layer of columnar or flattened
biliary-type epithelium. Also included in lists of sporadic hepatic cysts is the ciliated hepatic
foregut cyst, considered developmental in origin. These rare lesions are lined by pseudostratified
columnar epithelium with mucus cells; the underlying fibrous wall contains smooth muscle fibers .1
Perihilar cysts arise from periductal glands in the hepatic hilum and may be found in a variety of
conditions. They probably represent retention cysts from blockage of drainage of these periductal
glands. Generally asymptomatic, large perihilar cysts occasionally cause large duct obstruction.
The disorders known collectively as fibropolycystic diseases of the liver are characterized by
dilatation and varying degrees of fibrosis of different levels of the intrahepatic biliary tree. These
disorders include congenital hepatic fibrosis, Caroli's disease, Caroli's syndrome, multiple von
Meyenburg complexes, and polycystic liver disease; these may occur singly or in various combinations.
The essential precursor of the hepatic lesions is the failure of bile ductal plate remodeling during
embryogenesis. This ductal plate malformation may occur at different levels in the biliary tree, from
small interlobular bile ducts to large segmental ducts, thus leading to a spectrum of clinicopathologic
entities .2-5 Features in common include association with various cystic diseases of the kidney,
mendelian inheritance patterns, and increased risk of cholangiocarcinoma.
Embryology of the Intrahepatic Biliary System
Hepatic organogenesis begins in the fourth week of
gestation as the hepatic diverticulum forms from the ventral wall of the celphalad foregut. Formation of
the embryonic bile duct system begins in the eighth week of gestation, with intrahepatic bile duct cells
developing from precursor cells around the largest branches of the portal vein. These cells strongly
express cytokeratins 8, 18, and 19, and are duplicated over much of their length by a second epithelial
layer. First appearing near the hilum, the ductal plate over successive weeks forms around smaller and
smaller portal vein branches. After week 10, epithelial cells not involved in ductal plate formation
gradually lose cytokeratin 19 and express only hepatocyte-type cytokeratins. Around week 12, progressive
remodeling of ductal plates takes place, again starting in larger hilar portal tracts, with budding off
of part of the ductal plate epithelium to form interlobular bile ducts, and disappearance of the
epithelial elements of the remainder of the ductal plate .2-5 Components of the mesenchyme surrounding
the portal vein branches appear to be crucial to development of the intrahepatic biliary system and are
presumably important in ductal plate remodeling.
Congenital hepatic fibrosis is usually an autosomal recessive disorder, in most cases associated with
autosomal recessive polycystic kidney disease (ARPKD), but in this case paradoxically associated with
autosomal dominant polycystic kidney disease. It is characterized by persistence of the embryologic
ductal plate, with dilatation of the residual duct-like structures around the periphery of the portal
tract. Normal interlobular bile ducts may or may not be present. Extensive portal-portal bridging
fibrosis is usually present and may lead to an erroneous diagnosis of cirrhosis. However, in contrast to
cirrhosis, the hepatic parenchymal architecture is normal, without evidence of regeneration. Four forms
of congenital hepatic fibrosis are described, based on clinical presentation: portal hypertensive,
cholangitic, mixed, and latent. In young children with ARPKD, the renal symptoms may predominant and the
hepatic lesion may be discovered only upon investigation. The most common mode of presentation of the
liver disease is portal hypertension, with patients presenting as teen-agers with splenomegaly or
bleeding from esophageal varices. The isolated cholangitic form of congenital hepatic fibrosis is
uncommon. Many patients, as in this case, have the latent form of congenital hepatic fibrosis, found
incidentally in later life. The natural history of the disorder is often dominated by the renal disease
.6 Patients with portal hypertension may have normal growth and hepatic function. Those with the
cholangitic form are at greater risk for hepatic dysfunction.
Clinical Manifestations of Congenital Hepatic Fibrosis 7
|Type ||Manifestations ||Comments|
|Portal hypertensive ||splenomegaly, varices normal growth and liver function ||presents at age 5 years-13 years|
|Cholangitic ||Cholestasis, recurrent cholangitis poor growth; hepatic dysfunction ||Rare|
|Mixed ||Mixed ||More common than isolated cholangitic form|
|Latent ||None ||Renal disease dominates clinical picture|
Caroli's disease and Caroli's syndrome are both characterized by the presence of multiple saccular
dilatations of the larger segmental intrahepatic bile ducts. Caroli's syndrome combines this cyst
formation in large ducts with congenital hepatic fibrosis, and is thus thought to represent a sustained
insult to development of the intrahepatic biliary system. In contrast, Caroli's disease affects only
segmental bile ducts, and may be a result of an hereditary factor acting at a particular point in the
development of the biliary tree .2,4,5 The dilated ducts are subject to bile sludging and predispose
to multiple bouts of cholangitis. Continued obstruction may lead to secondary biliary cirrhosis.
Approximately 15% of cases involve only a portion of the liver, most commonly the left lobe; such cases
are amenable to surgical resection. An increased risk of cholangiocarcinoma is reported, and amyloidosis
may occur as a result of chronic infection.
Von Meyenberg Complexes
These small lesions, also called bile duct hamartomas, are generally
asymptomatic and are often diagnosed during intraoperative frozen section consultation or at autopsy.
When multiple, they may represent the forme fruste of polycystic liver disease. The von Meyenburg
complex consists of dilated biliary channels, sometimes containing inspissated bile, embedded in fibrous
stroma at the periphery of a portal tract. Although it was previously thought that von Meyenburg
complexes did not communicate directly with the biliary tree, recent studies have shown their continuity
with the intrahepatic bile ducts, thus supporting origin from the ductal plate. The lesion probably
represents a slowly involuting remnant of the ductal plate of a small peripheral interlobular bile duct
.2,4 Multiple von Meyenburg complexes are found in polycystic liver disease, and give rise to the
macroscopic cysts of that disorder. They are in rare instances associated with cholangiocarcinoma .8
Polycystic Liver Disease
Patients with polycystic liver disease usually have ADPKD. The liver
cysts are not present at birth, but develop over time as fluid accumulates in the dilated biliary spaces
of von Meyenburg complexes. Up to 30% of young adults will have liver cysts; this prevalence increases
to 90% in older patients. Multiple unilocular cysts resembling simple biliary cysts and ranging in size
from a few millimeters to over 10 cm in diameter are scattered diffusely throughout the liver. The cysts
usually do not compromise hepatic function but may produce hepatomegaly and abdominal discomfort. Women
are more likely to be symptomatic from the cysts, and morbidity is related to number of pregnancies, use
of oral contraceptives, and severity of renal involvement .9
The currently favored theory for the pathogenesis of the fibropolycystic disorders is
that a single gene defect causes maturational arrest of biliary and renal tubular epithelial cells.
Approximately 95% of autosomal dominant polycystic kidney disease has been linked to mutations in one of
two genes. PKD1, located on chromosome 16 and mutated in 85% of patients with ADPKD, encodes an integral
membrane glycoprotein, polycystin-1. The second gene implicated in ADPKD, PKD2, is responsible for 5 to
10% of cases and is located on chromosome 4. PKD2 also encodes an integral membrane protein, known as
polycystin-2. Patients with PKD2 mutations are similar clinically to patients with PKD1 mutations, but
present later in life with renal disease .10 Germline mutations in these genes are inactivating.
While ADPKD is inherited in a dominant fashion, it is believed that the disease is recessive on a
cellular level, in that loss of the wild-type allele in renal or hepatic epithelial cells (the second hit
hypothesis) is necessary for cyst formation .11,12 Mice with targeted mutations of either gene die in
embryogenesis, suggesting that these genes are required for normal fetal development. Polycystin-1 is
involved in cell-cell or cell-matrix interactions with other proteins, possibly via E-cadherin and a , b
, and g -catenins. Polycystin-2 is thought to function as a subunit of an ion channel whose activity is
regulated by polycystin-1. It is postulated that polycystin-2 forms complexes with itself, polycystin-1,
or some unknown protein to function as an ion channel .10 In view of this hypothesis, it is
interesting that the coexistence of cystic fibrosis and ADPKD appears to reduce or delay formation of
renal and hepatic cysts .13 The interaction of polycystin-1 and polycystin-2 may serve to explain the
nearly identical shared phenotype associated with mutations in these genes.
Abnormally elevated expression of the proto-oncogenes c-myc, c-fos, and c-Ki-ras has been
demonstrated in cyst epithelium in polycystic kidneys. This altered expression may reflect a
maturational arrest in renal tubulo-epithelial cells, with loss of polarization and increased
proliferative capacity. It is postulated that dysregulated proliferation of the epithelial cells leads
to cyst formation .5 Defective remodeling of the ductal plate probably results in the distinctive
hepatic lesions, although the dominant role of the portal vein branches in development of the biliary
tree must also be considered, and it is likely that mesenchyme-epithelial cell interaction also plays a
role in the pathogenesis of these lesions. Further clarification of these disorders will depend on
Cystic dilatation of the common bile duct, or choledochal cyst, is generally
considered a congenital disorder, although reflux of pancreatic juices into the bile duct because of an
anomalous pancreaticobiliary junction has also been implicated. Classification is based on anatomic
location and extent. Microscopically, the cyst wall is fibrotic and variably inflamed. The biliary
epithelial lining is often denuded; goblet cell metaplasia and squamous metaplasia have been described.
Complications include biliary obstruction, cholangitis, cirrhosis, and cholangiocarcinoma. Complete
surgical excision is the treatment of choice.
Classification of Choledochal Cysts 14
|Type ||Features ||Comments|
|I ||Segmental or diffuse dilatation of common bile duct ||Most common form|
|II ||Diverticulum, usually of lateral wall|| |
|III ||Choledochocele, usually in duodenal wall ||Usually lined by duodenal mucosa|
|IV-A ||Multiple extrahepatic duct cysts ||In association with intrahepatic cysts (Caroli's disease)|
|IV-B ||Multiple extrahepatic duct cysts ||Without associated intrahepatic cysts|
- Vick DJ, Goodman ZD, Deavers MT, Cain J, Ishak KG. Ciliated
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- Wu G, d'Agati V, Cai Y, Markowitz G, et al. Somatic inactivation of Pkd2 results in
polycystic kidney disease. Cell 93:177-88, 1998.
- Watnick TJ, Torres VE, Gandolph MA, Qian F, et al. Somatic mutation in individual
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Molecular Cell 2:247-51, 1998.
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- Matsumoto Y, Uchida K, Nakase A, Houjo I. Clinicopathologic classification of
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