—  SHORT COURSE  —

Disorders of the Intra- and Extrahepatic Bile Ducts

Case 9 - Caroli's Disease

Kay Washington, M.D., Ph.D.
Pathology, C-3321 MCN
Vanderbilt University Medical Center
Nashville, TN 37232-2561


Clinical History
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.

Morphologic Findings

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:

Slide 21
Caroli's Disease
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.
Slide 22
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 

Pathogenesis
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 genetic studies.



Choledochal Cyst
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

References

  1. Vick DJ, Goodman ZD, Deavers MT, Cain J, Ishak KG. Ciliated hepatic foregut cyst: a study of six cases and review of the literature. Am J Surg Pathol 23:671-7, 1999.
  2. Desmet VJ. Ludwig symposium on biliary disorders- part I. Pathogenesis of ductal plate abnormalities. Mayo Clinic Proceedings 73:90-9, 1998.
  3. Desmet VJ. What is congenital hepatic fibrosis? Histopathology 20: 465-77, 1992.
  4. Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme "ductal plate malformation". Hepatology 16: 1069-83, 1992.
  5. D'Agata IAD, Jonas MM, Perez-Atayde AR , Guay-Woodford LM. Combined cystic disease of the liver and kidney. Seminars in Liver Disease 14: 215-228, 1994.
  6. Perisic VN. Long-term studies on congenital hepatic fibrosis in children. Acta Paediatr 84: 695-6, 1995.
  7. Jonas MM. Congenital hepatic fibrosis and other fibropolycystic diseases. In: Diseases of the Bile Ducts: Pathogenesis, Pathology and Practice. American Association for the Study of Liver Diseases Postgraduate Course, 1996: 49-56.
  8. Jain D, Sarode VR, Abdul-Karim FW, Homer R, Robert ME. Evidence for the neoplastic transformation of Von-Meyenberg complexes. Am J Surg Pathol 24:1131-9, 2000.
  9. Gabow PA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 11:1033-7, 1990.
  10. Bacallao RL, Carone FA. Recent advances in the understanding of polycystic kidney disease. Curr Opin Nephrol Hypertens 6:377-83, 1997.
  11. 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.
  12. Watnick TJ, Torres VE, Gandolph MA, Qian F, et al. Somatic mutation in individual liver cysts supports a two-hit model of cytogenesis in autosomal dominant polycystic kidney disease. Molecular Cell 2:247-51, 1998.
  13. O'Sullivan DA, Torres VE, Gabow PA, Thibodeau SN, King BF, Bergstrahl EJ. Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease. Am J Kidney Dis 32: 976-83, 1998.
  14. Matsumoto Y, Uchida K, Nakase A, Houjo I. Clinicopathologic classification of congenital cystic dilatation of the common bile duct. Am J Surg 134:569-74, 1977.