Caroli’s Disease: Education About a Rare Inherited Disorder
Q: What Do I Need to Know?
A: Cystic lesions of the hepatobiliary system are being increasingly diagnosed. These fibropolycystic diseases involve multiple organs. They are usually inherited and occur in various combinations, consisting of polycystic liver disease, microhamartoma, congenital hepatic fibrosis, Caroli’s disease and choledochal cysts. Caroli’s disease, originally described by Jacques Caroli in 1958, is a congenital disorder characterized by multiple segmental or saccular dilatations of the large intrahepatic bile ducts. Caroli’s syndrome is a congenital disorder characterized by multiple segmental or saccular dilatations of the intrahepatic bile ducts associated with congenital hepatic fibrosis. The term congenital fibrosis refers to a unique congenital liver histology characterized by bland portal fibrosis, hyperproliferation of interlobular bile ducts within the portal areas with variable shapes and sizes of bile ducts, and preservation of the normal lobular architecture.
More than 200 cases with equal frequencies in males and females have been reported in the literature from United Kingdom, France, Japan, and the United States with Caroli’s syndrome occurring more than the pure form of Caroli’s disease. Symptoms appear first in adults, though childhood and neonatal cases have been reported.
The most accepted theory is related to ductal plate malformations at different levels of the intrahepatic biliary tree. The formation of the ductal plates follows the branching growth of the portal vein from the hilus to the periphery, as does the remodeling of the ductal plates which begins from the larger to smaller ducts. Thus hereditary factors influencing Caroli’s syndrome influence the early embryonic development of the large intrahepatic bile duct formation as well as the development of the more proximal intralobular ducts related with congenital hepatic fibrosis.
The molecular pathogenesis is not clear. It appears to be inherited in an autosomal recessive manner, associated with autosomal recessive polycystic kidney disease (ARPKD). The gene mapped to chromosome 6 (6p21-p12) is called the PKHD1 gene (for polycystic kidney and hepatic disease 1). It encodes for a large protein (4074 amino acids) called fibrocystin, which is involved in regulation of cell proliferation, cellular adhesions, repulsion, and ciliary function.
Mutations in two different genes, polycystic kidney disease (PKD) 1 or 2, give rise to an autosomal dominant polycystic kidney disease (ADPKD), which in rare cases is associated with Caroli’s disease. Products of PKD genes (polycystin 1 and polycystin 2) are involved in cell–cell or cell–matrix interactions. Polycystin 1 is expressed in the liver including biliary system and kidney and is likely involved in embryogenesis.
As previously described, the biliary abnormality consists of segmental, saccular dilatations of the large intrahepatic bile ducts, which are in continuity with the rest of the biliary tree. The disease may be limited to 1 lobe of the liver, more commonly the left.
The dilated bile ducts are lined by biliary epithelium which may be hyperplastic and ulcerated. In Caroli’s syndrome, the additional findings of congenital hepatic fibrosis characterized by bland portal fibrosis, hyperproliferation of interlobular bile ducts within the portal areas with variable shapes and sizes of bile ducts, and preservation of the normal lobular architecture are seen (Figure 1).
The clinical features of Caroli’s syndrome are a combination of Caroli’s disease (bile stasis, recurrent bouts of cholangitis, hepatolithiasis, gallbladder stones, and increased risk of cholangiocarcinoma) and those of congenital hepatic fibrosis (including portal hypertension and variceal bleeds). ARPKD frequently presents in neonates and can even be detected in utero. The symptoms may develop early or late in life. Consequences of congenital hepatic fibrosis like portal hypertension appear later in the disease process indicating that Caroli’s syndrome has a progressive course. The complications of portal hypertension include ascites and esophageal varices which may present with hematemesis and malena. Patients may present with intermittent abdominal pain and pruritis associated with hyperbilirubinemia. In Caroli’s disease and syndrome, the saccular dilatations predispose to bile stagnation, biliary sludge, and intraductal lithiasis, which may result in chronic abdominal pain and pancreatitis. Bacterial cholangitis occurs frequently, complicated by septicemia and hepatic abscess formation. This remains the major cause of morbidity and mortality.
On examination, there may be hepatosplenomegaly from portal hypertension. Enlarged kidneys may be palpable with renal involvement. Laboratory analysis may include: alanine aminotransferase (ALT), alkaline phosphatase and bilirubin elevations, thrombocytopenia, and leukopenia if portal hypertension and hypersplenism are present. Leukocytosis may indicate cholangitis. An elevation of the blood urea nitrogen and creatinine should suggest underlying renal disease associated with this disorder. On occasion, coagulopathy may be found related to vitamin K malabsorption in cholestatic patients.
Transabdominal imaging may reveal intrahepatic cystic anechoic areas in which fibrovascular bundles, stones, and linear bridging may be seen (Figure 2).
Doppler sonogram may be useful by demonstrating flow within fibrovascular bundles composed of the portal vein and hepatic artery and may also be useful to follow the progression of fibrosis in patients with Caroli’s syndrome.
Although there is a risk for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, ERCP remains the gold standard for the evaluation of the biliary tree. The risks and benefits of this procedure need to be considered prior. In complex difficult cases of fusiform dilatation of the biliary tract, ERCP may show communication between sacculi and bile ducts and diverticulum-like sacculi of the intrahepatic biliary tree (Figure 3).
Computed tomography may be helpful. Although nonspecific, it may show saccular and fusiform dilatations of intrahepatic bile ducts (Figure 4). Fibrovascular bundles are seen as enhancing central dots (dot sign), septa, and nodules. Renal cysts may also be seen. A cirrhotic liver with signs of marked portal hypertension, which include ascites, splenomegaly, esophageal and splenic varices, and patent paraumbilical vein may be seen (Figure 5).
Magnetic resonance imaging is the best noninvasive imaging technique to confirm large or small cystic patterns. Combined with the use of gadolinium, it may allow visualization of the dot sign, which is very specific for malformations of the ductal plate.
A liver biopsy is not required to establish a diagnosis of Caroli’s syndrome, but when obtained, it will show intrahepatic bile duct ectasia and proliferation associated with severe periportal fibrosis, confirming the congenital hepatic fibrosis component of Caroli’s syndrome. In Caroli’s disease, there is only ectasia of the larger hepatic ducts. Liver biopsy may show features of cholangitis.
The differential diagnosis of cystic diseases of the liver include Caroli’s syndrome, polycystic liver disease, obstructive biliary disease, primary sclerosing cholangitis, biliary papillomatosis and choledochal cysts.
Caroli’s syndrome belongs to a family of polycystic diseases, involving other organs; renal involvement is seen in 60% of cases. This manifests as dilatation of the collecting renal tubules, renal tubular ectasia, adult recessive polycystic disease, and rarely adult dominant polycystic kidney disease. Congenital heart disease, pulmonary hypertension with arteriovenous fistula, pulmonary fibrosis and cavernomatous transformation of portal vein may be also found.
Complications of this disease include cholangitis, choledocholithiasis, hepatic abscesses, cholangiocarcinoma (seen in 7% to 14% of patients), cirrhosis, portal hypertension and liver failure. The treatment of complications associated with Caroli’s syndrome involves the use of medical, endoscopic and surgical modalities. The medical management involves the use of antibiotics for acute cholangitis. Ursodeoxycholic acid is used in chronic cholestasis to decrease bile stasis and increase bile flow and in some cases is associated with dissolution of bile duct stones. Supportive care includes vitamin supplementation of fat-soluble vitamins in patients with chronic cholestasis. In cases of portal hypertension and varices, nonselective beta-blockers are prescribed. In the treatment of variceal hemorrhage, blood transfusions, antibiotics, somatostatin infusions, and endoscopic variceal banding are required. Transjugular intrahepatic porto-systemic shunts, surgical port-caval shunts are considered in patients not responsive to band ligation or sclerotherapy.
Endoscopic management for drainage of bile involves the use of ERCP with possible sphincterotomy and stone removal. Drainage during percutaneous transhepatic cholangi- ography is another option. Imaging modalities are used to plan surgical treatment. If one lobe of the liver is involved, then hepatic resection is curative. Internal bypass procedures like choledochojejunostomy and Roux-en-Y hepaticojejunostomy are used for diffuse disease. Liver or dual liver-kidney transplantation is curative in both Caroli’s disease and Caroli’s syndrome with kidney involvement. Since the disease has an autosomal recessive transmission, family genetic counseling is important.
The prognosis is variable depending upon the severity of symptoms and other organs involved. Increased morbidity is associated with recurrent cholangitis. There is an increased risk of 7% to 14% of developing cholangiocarcinoma. Amyloidosis has been seen in chronic or recurrent cholangitis. Liver transplantation offers a curative option in refractory disease.
Tenner S, Brown A, Gress FG. Curbside Consultation of the Pancreas: 49 Clinical Questions. (pp 203-208). ©2010 SLACK Incorporated.
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