Pediatric Caroli Disease 

Updated: Oct 20, 2017
Author: Mutaz I Sultan, MBChB, MD; Chief Editor: Carmen Cuffari, MD 

Overview

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. This process can be either diffuse or segmental and may be limited to one lobe of the liver, more commonly the left lobe.

Caroli disease is sporadic, whereas Caroli syndrome is generally inherited in an autosomal recessive manner.[1]  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. See the image below.

Hepatic ultrasonogram of a neonate with Caroli dis 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.

Pathophysiology

The precursor of the intrahepatic biliary tree is a sheath of cells surrounding the portal vein branches, known as the ductal plate (DP). The DP first arises from hepatocyte precursors surrounding hilar portal vein vessels at 8 weeks' gestation, and more peripheral regions of the DP develop sequentially. During the remainder of gestation, a process of DP remodeling occurs, during which 1-2 ductules form at points along the circumference of the DP that connect to the intrahepatic biliary tree; the remaining regions of the DP are lost, most likely through apoptosis. Caroli syndrome belongs to a subcategory of diseases thought to originate from DP 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.[1] . Because reports have described cases limited to the left lobe of the liver, some have described Caroli disease as either localized or diffuse. 

In Caroli syndrome, DP 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 belong in the same spectrum of disease as congenital hepatic fibrosis and ARPKD.

Another classification of Caroli disease is type I, or simple Caroli disease, which consists of pure cystic dilatations of the intrahepatic bile ducts; type II, or complex Caroli disease, is also known as Caroli’s syndrome.[2]

 

Epidemiology

Frequency

United States

Caroli disease and Caroli syndrome are very rare, with an estimated incidence of less than 1 case per 100,000 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).

The incidence of ARPKD/congenital hepatic fibrosis is approximately 1:20,000 live births.[3]

Mortality/Morbidity

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

Age at presentation varies and patients may present as neonates or as adults. Cases detected in utero based on ultrasonographic findings have been reported.

 

Presentation

History

The mode of presentation depends on the age of onset and the predominance of renal or hepatic involvement. Children with Caroli syndrome usually have an earlier onset of symptoms and a more progressive disease, given of the effects of both cholangitis and portal hypertension.

Patients with Caroli disease or Caroli syndrome may have a history of intermittent abdominal pain, which reflects episodes of bile stasis or the passage of bile stones. Patients may report pruritus secondary to cholestasis. Patients with cholangitis may report fever and pain in the right upper quadrant.

In Caroli syndrome, portal hypertension may result in hematemesis or melena secondary to bleeding varices. Patients may also develop ascites in association with portal hypertension. Most (64%) patients who have portal hypertension have autosomal recessive polycystic kidney disease (ARPKD).[3]

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

The following may be observed:

  • 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 on chromosome 6p21, which is the gene linked to ARPKD, have been identified in patients with Caroli syndrome.

PKHD1 encodes the protein fibrocystin, which is expressed in cortical and medullary ducts in the kidney as well as biliary and pancreatic ducts in a pattern consistent with the histologic patterns seen in ARPKD.

Fibrocystin is one of a larger family of proteins that are present in the primary cilium.

Recent research supports a mechanistic link between ciliary dysfunction and polycystic kidney disease, although this remains controversial. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) in a rat model appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation.[4]

The number of cases of Caroli syndrome caused by PKHD1 mutations is not known.

Caroli syndrome is inherited in an autosomal recessive manner.

 

DDx

 

Workup

Laboratory Studies

Bilirubin levels are usually in the reference range in patients with Caroli disease or Caroli syndrome.

Transaminase levels may be slightly elevated.

The CBC count may reveal thrombocytopenia and leukopenia if portal hypertension and hypersplenism are present. An elevated WBC count or erythrocyte sedimentation rate (ESR) may indicate cholangitis.

Coagulation profile may reveal a coagulopathy secondary to cholestasis and vitamin K malabsorption or due to poor hepatic synthetic function.

Creatinine and BUN values should be obtained to detect associated renal disease.

Carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) are used to screen for cholangiocarcinoma.[5]

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 Caroli 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 Caroli syndrome. It provides excellent images of the intrahepatic and extrahepatic biliary trees and 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 ultrasonography cannot be performed because of bowel gas or body habitus. It can reveal multiple cystic dilatations of the intrahepatic bile ducts. The central dot sign involves enhancing dots within the dilated intrahepatic bile ducts, representing portal radicles.[4]

Hepatobiliary scintigraphy can be useful to document communication between cysts and the biliary system, a feature present in Caroli disease or Caroli 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. ERCP can also be of therapeutic use for stone extraction, sphincterotomy, or biliary stenting.

Procedures

Blood culture should be performed in cases of suspected chronic cholangitis.

When obtained in Caroli syndrome, liver biopsy shows bands of mature fibrosis tissue and distorted bile ducts characteristic of congenital hepatic fibrosis.

ERCP has been used to identify and treat biliary stones in patients with Caroli disease or Caroli syndrome but is associated with postprocedural risks, including pancreatitis or 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 (DP) 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, without associated hepatic fibrosis.

Other Tests

The identification of the PKHD1 gene in patients with autosomal recessive polycystic kidney disease (ARPKD) has provided a basis for gene-based diagnostic testing. Several studies have analyzed PKHD1 and have reported more than 300 mutations, with the mutation detection rate varying 42-87%.[6]

 

Treatment

Approach Considerations

The management is for complications of portal hypertension and cholangitis because these are the main presenting features in children.

Medical Care

Ursodeoxycholic acid can decrease the frequency of Caroli disease complications due to cholelithiasis. Broad-spectrum antibiotic coverage, including anaerobic coverage, is indicated in cases of cholangitis. Patients with cholestasis should receive fat-soluble vitamin supplementation. Because patients with Caroli syndrome or Caroli disease are at an increased risk for cholangiocarcinoma, initial radiographic (ie, ultrasonography, MRI) and serologic (ie, CA19-9, CEA) screening should be performed.

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. Liver transplantation may be indicated in severe cases of refractory or chronic cholangitis, liver failure, or malignant transformation.[7]

Liver transplantation represents an uncommon indication for Caroli disease. Excellent results have been reported, as shown by multicentric European and American registry reports.[8]

Isolated or combined kidney and liver transplantations have become available for children with polycystic liver and kidney disease. Immunosuppression after isolated renal transplantation may lead to an increased number of episodes of cholangitis and worsening liver condition. Therefore, a combined liver-kidney transplantation may be required in children with established end-stage renal failure and advanced chronic liver disease.[9]

 Patients who have developed esophageal varices should receive prophylaxis with a nonselective beta-blocker and variceal endoscopic therapy. The shunting procedure can provide relief from portal hypertension because liver function may be well preserved.

 

 

Medication

Medication Summary

Ursodiol can promote the dissolution of intrahepatic stones and promote bile flow in Caroli disease or Caroli syndrome. Broad-spectrum antibiotics are used in the treatment of cholangitis associated with Caroli disease or Caroli syndrome.

Gallstone dissolution agents

Class Summary

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.

Ursodiol (Urso, Actigall)

Also called ursodeoxycholic acid. Naturally occurring bile used to dissolve radiolucent gallstones. Suppresses hepatic cholesterol synthesis, cholesterol secretion, and inhibits cholesterol intestinal absorption. Little inhibitory effect on synthesis and secretion into bile of endogenous bile acids and does not appear to affect phospholipid secretion into bile. Alters bile composition from supersaturated to unsaturated. Ursodiol-rich bile solubilizes cholesterol by increasing the concentration level at which cholesterol saturation occurs. Promotes bile flow in cholestatic conditions associated with patent extrahepatic biliary system.

Antibiotic agents

Class Summary

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.

Ampicillin and sulbactam (Unasyn)

Drug combination of beta-lactamase inhibitor with ampicillin. Used to treat infections involving skin, enteric flora, and anaerobes. Provides broad gram-positive and anaerobic coverage. Should be combined with an agent with gram-negative coverage, such as aminoglycoside.

Gentamicin (Garamycin)

Used to treat cholangitis. Aminoglycoside antibiotic for gram-negative coverage. Used in combination with an agent against gram-positive organisms and one that covers anaerobes.

 

Follow-up

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 CA19-9 and CEA is one approach, although the benefit of such screening has not been tested. CEA is relatively nonspecific and can be elevated in other bile duct pathologies such as cholangitis and hepatolithiasis. Although CA19-9 is more specific, it can also be elevated in benign bile duct disease.

Some promising studies have investigated the use of new tumor markers such as matrix metalloproteinase-7 (MMP-7) to differentiate between benign bile duct disease and cholangiocarcinoma. Further investigation is required before these markers can be recommended.

Further Inpatient Care

Indications for hospitalization in patients with Caroli disease are as follows:

  • Suspected cholangitis or sepsis

  • Obstructing cholelithiasis requiring invasive intervention

  • Complications of end-stage liver disease

Prognosis

Prognosis depends on the specific manifestations.

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 determine 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 cirrhosis and portal hypertension.

The risk of cholangiocarcinoma in individuals with Caroli disease or Caroli syndrome 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.

Liver transplantation in patients with Caroli disease or Caroli syndrome is indicated in patients with refractory disease or with complications of hepatic fibrosis and is associated with excellent outcomes and long-term survival. Patients undergoing combined liver and kidney transplantation rather than liver transplantation alone generally have better outcomes.[10, 11]

Renal manifestations

The degree of polycystic kidney disease associated with Caroli syndrome varies. Patients who present with renal disease as neonates or infants are more likely to have severe kidney 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.