AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Caroli disease and Caroli syndrome are rare congenital disorders of the intrahepatic bile ducts. They are both characterized by dilatation of the intrahepatic biliary tree. The term Caroli disease is applied if the disease is limited to ectasia or segmental dilatation of the larger intrahepatic ducts. This form is less common than Caroli syndrome, in which malformations of small bile ducts and congenital hepatic fibrosis are also present. Caroli disease is sporadic, whereas Caroli syndrome is generally inherited in an autosomal recessive manner. As with congenital hepatic fibrosis, Caroli syndrome is often associated with autosomal recessive polycystic kidney disease (ARPKD). A rare association with autosomal dominant polycystic kidney disease (ADPKD) has also been reported.

Pathophysiology

The precursor of the intrahepatic biliary tree is a double-layered sleeve of cells known as the ductal plate (DP). The DP first arises from hepatocyte precursors surrounding hilar portal vein vessels at 8 weeks gestation, and peripheral regions of the DP then develop sequentially. During the remainder of gestation, a process of DP remodeling occurs in which small areas of the double layer separate to form tubules, which join to form the intrahepatic biliary tree, while the remaining regions of the DP are lost, most likely through apoptosis. Caroli syndrome belongs to a subcategory of diseases thought to originate from failures of this process collectively known as ductal plate malformation.

In Caroli disease, abnormalities of the bile duct occur at the level of the large intrahepatic ducts (ie, left and right hepatic ducts, segmental ducts), resulting in dilatation and ectasia. Resulting biliary stasis may lead to cholelithiasis, cholangitis, and sepsis, as well as an increased risk of cholangiocarcinoma.

In Caroli syndrome, ductal plate malformation is present at the level of the smallest portal tracts and is associated with varying degrees of portal fibrosis. These findings are typical of congenital hepatic fibrosis; therefore, Caroli syndrome is thought to exist in the same spectrum of disease as congenital hepatic fibrosis. As with congenital hepatic fibrosis, the pathology may also include features of ARPKD.

Frequency

United States

Caroli disease and Caroli syndrome are very rare, with an estimated incidence of 1 case per 1,000,000 population. Caroli syndrome (ectasia of the large and small bile ducts with congenital hepatic fibrosis) is more common than Caroli disease (ectasia of only the large bile ducts).

Mortality/Morbidity

Patients with Caroli disease or syndrome may have recurrent episodes of cholangitis and are also at risk for associated bacteremia and sepsis.

• Patients with Caroli syndrome may have cholangitis, as do those with Caroli disease; however, they may also have the complications of portal hypertension observed in congenital hepatic fibrosis.
• Caroli syndrome is associated with ARPKD, and patients may have various degrees of renal cysts, interstitial fibrosis, and renal failure.
• Both Caroli disease and Caroli syndrome are associated with a risk of cholangiocarcinoma at a rate of 100 times that of the general population.

Sex

Symptoms of Caroli disease or syndrome are more common in female patients than in male patients.

Age

Symptoms appear first in adults, though childhood and neonatal cases have been reported. Cases of prenatal diagnosis based on ultrasonographic findings have been reported.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The patient may have a history of intermittent abdominal pain, which reflects episodes of bile stasis or the passage of bile stones.
• Patients with cholangitis may report fever and pain in the right upper quadrant.
• In Caroli syndrome, portal hypertension may result in hematemesis or melena.
• Because Caroli syndrome is associated with ARPKD and is inherited in an autosomal recessive manner, the patient may have a family history of kidney or liver disease.

Physical

• Hepatomegaly may be present.
• Splenomegaly may be present if portal hypertension occurs.
• Tenderness of the right upper quadrant is occasionally present.
• Abdominal mass or masses occur if large polycystic kidneys are present.
• Jaundice is rarely present.

Causes

• A genetic cause is likely, given the association with ARPKD.
• • Mutations in PKHD1, the gene linked to ARPKD have also been identified in patients with Caroli syndrome.
  • The number of cases of Caroli syndrome caused by PKHD1 mutations is not known.
• Caroli syndrome appears to be inherited in an autosomal recessive manner.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Cholangitis
Choledochal cyst
Polycystic liver disease
Hepatic abscesses

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Bilirubin levels are usually in the reference range.
• Transaminase levels may be slightly elevated.
• The CBC may reveal thrombocytopenia and leukopenia if portal hypertension and hypersplenism are present. An elevated WBC count or erythrocyte sedimentation rate (ESR) may indicate cholangitis.
• Creatinine and BUN values should be obtained to detect associated renal disease.

Imaging Studies

• Ultrasonography is the best initial imaging study because it reveals the irregular dilatation of the large intrahepatic bile ducts typical of Caroli disease or syndrome.
• • Extrahepatic biliary dilatation may also be present as a result of prior cholelithiasis.
  • Doppler evaluation of the liver can be used to detect portal hypertension.
  • The kidneys can also be assessed for evidence of polycystic kidney disease.
• Magnetic resonance cholangiography is increasingly used to diagnose Caroli disease or syndrome.
• • It provides excellent images of the intrahepatic and extrahepatic biliary trees, and it can also depict renal involvement.
  • Its use is currently limited by the availability of the necessary equipment and expertise.
• CT may be used, particularly if sonograms cannot be obtained because of bowel gas or body habitus.
• Hepatobiliary scintigraphy can be useful to document communication between cysts and the biliary system, a feature present in Caroli disease or syndrome but absent in polycystic liver disease and hepatic abscesses.
• Invasive modalities, such as percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP), enable excellent visualization of the biliary tree. However, these studies are limited by the risks of complications.

Procedures

• Liver biopsy and culture should be performed in cases of suspected chronic cholangitis.
• ERCP has been used to identify and treat biliary stones in patients with Caroli disease or syndrome, but it is associated with a postprocedural risk of cholangitis.
• Portosystemic shunting may be indicated in patients who have portal hypertension.

Histologic Findings

In Caroli syndrome, the liver biopsy reveals typical findings of ductal plate malformation, with ducts arranged in a circumferential pattern around the portal vein branches and with a variable degree of associated portal fibrosis. In Caroli disease, only large intrahepatic ducts are affected.

TREATMENT

Section 6 of 11  

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Medical Care

Ursodeoxycholic acid can decrease the frequency of complications due to cholelithiasis. Broad-spectrum antibiotic coverage, including anaerobic coverage, is indicated in cases of cholangitis.

Surgical Care

Surgical treatment may be necessary for recurrent or refractory cholangitis. Obstructing stones can be removed and bile flow can be maintained by means of a hepaticojejunostomy or external drainage.

• In cases of localized stasis, lobectomy can be curative and can also reduce the risk of cholangiocarcinoma.
• In severe cases of refractory or chronic cholangitis or in cases of liver failure, transplantation may be considered.

MEDICATION

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Ursodiol can promote the dissolution of intrahepatic stones and promote bile flow in Caroli disease or syndrome.

Broad-spectrum antibiotics are used in the treatment of cholangitis associated with Caroli disease or syndrome.

Drug Category: Gallstone dissolution agents

These agents are used to prevent and possibly to dissolve gallbladder stones. They enhance bile salt–dependent biliary flow. They also act as choleretic agents and may prove to be a valuable addition to therapy in repeated and refractory cholangitis.

Drug Category: Antibiotic agents

Broad-spectrum antibiotics are used to treat cholangitis. Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Indications for hospitalization
• • Suspected cholangitis or sepsis
  • Obstructing cholelithiasis requiring invasive intervention
  • Complications of end-stage liver disease

Further Outpatient Care

• Liver function and transaminase levels can be monitored on an outpatient basis.
• Ultrasonography can be used to monitor stones.
• No guidelines have been established regarding monitoring for the development of cholangiocarcinoma. Annual evaluation by MRI and measurement of CA-19-9 and carcinoembryonic antigen (CEA) is one approach, although the benefit of such screening has not been tested.

Prognosis

• Hepatic manifestations
• • In the few patients who have intrahepatic ductal ectasia without associated congenital hepatic fibrosis (ie, Caroli disease), the frequency and severity of episodes of cholangitis, which may result in sepsis or death, largely determines the prognosis. Progressive liver failure may also develop, and liver transplantation may be required.
  • Patients with both ductal ectasia and congenital hepatic fibrosis (ie, Caroli syndrome) are subject to the risks and consequences of recurrent cholangitis, as described above. They are also at risk for the complications of portal hypertension, namely, variceal bleeding, hypersplenism, and thrombocytopenia.
  • The risk of cholangiocarcinoma in individuals with Caroli disease is estimated to be 100-fold higher than the general population. Cholangiocarcinoma following resection of Caroli disease or syndrome confined to a single lobe has not been reported.
• Renal manifestations
• • The degree of polycystic kidney disease associated with Caroli disease or syndrome is variable.
  • Patients who present with renal disease as neonates or infants are more likely to have severe disease with enlarged cystic kidneys and progressive renal failure than others.
  • Other patients may have normal-appearing kidneys or minimal cystic changes with only mild deficits in renal function.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Patients with Caroli disease or syndrome should be screened for associated renal anomalies and impaired renal function.

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Hepatic ultrasonogram of a neonate with Caroli disease. Multiple dilated intrahepatic bile ducts are present. Courtesy of Richard Bellah, MD, The Children's Hospital of Philadelphia.
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Media type:  Image

REFERENCES

Section 11 of 11

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• Introduction
• Clinical
• Differentials
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• Sanzen T, Harada K, Yasoshima M, et al. Polycystic kidney rat is a novel animal model of Caroli's disease associated with congenital hepatic fibrosis. Am J Pathol. May 2001;158(5):1605-12. [Medline]. [Full Text].
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• Sgro M, Rossetti S, Barozzino T, et al. Caroli's disease: prenatal diagnosis, postnatal outcome and genetic analysis. Ultrasound Obstet Gynecol. Jan 2004;23(1):73-6. [Medline].
• Sleisenger MH, Fordtran JS, Feldman M, et al. Anatomy, anomalies, and pediatric disorders of the biliary tract. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. WB Saunders Co; 1993:917-927.
• Suchy FJ. The cholangiopathies. In: Sokol RJ, Balistreri WF, eds. Liver Disease in Children. Philadelphia, Pa: Lippincott Williams & Wilkins; 1994:153-65.
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Article Last Updated: Sep 10, 2007