Caroli Disease

Etiology

Caroli disease is thought to arise from abnormal embryologic development characterized by ductal plate malformations. The formation of the intrahepatic bile duct system involves the development of the ductal plate, a group of cells that forms around the portal vein branches. During week 12 of gestation, remodeling of the ductal plate leads to the formation of large intrahepatic bile ducts. An arrest in this remodeling process results in Caroli disease.[4]

Ductal plate remodeling is a continuous process of forming bile duct branches in descending size—hepatic, segmental, area, intralobular, and the smallest duct branches. Malformation of the ductal plate can continue to later stages of development, affecting the formation of peripheral or small bile ducts in Caroli syndrome.[13][4] Notably, in contrast to Caroli disease, Caroli syndrome is inherited in an autosomal recessive pattern and commonly occurs concurrently with ARPKD. Both conditions involve mutations in the PKDH1 gene on chromosome 6 (6p12.3-p12.2), and more than 100 mutations have been reported. The PKDH1 gene encodes fibrocystin—a protein primarily expressed in the kidney, with lower expression levels observed in the liver and pancreas.[2][14]

Epidemiology

The estimated prevalence of Caroli disease is approximately 1 case per 1,000,000 people. Caroli syndrome is more common, with an estimated prevalence of 1 in 10,000 to 20,000 live births. Both males and females are equally affected, and the condition is more prevalent among individuals of Asian descent. Over 80% of patients are symptomatic and are subsequently diagnosed before the age of 30.[1][15][5]

Pathophysiology

In Caroli disease, the arrest of the large bile duct during development results in the formation of an intrahepatic cyst. While these cysts affect morphology, liver function is preserved. The cystic dilation of intrahepatic bile ducts may affect a particular liver segment or lobe or involve the entire liver. These malformed bile ducts are significantly dilated and prone to biliary sludge formation and intrahepatic lithiasis, creating a predisposition for infection and recurrent cholangitis. Rarely, recurrent cholangitis and secondary chronic epithelial damage may progress to biliary cirrhosis.[14] 

While the exact pathophysiology of Caroli disease is not fully understood, research has highlighted the crucial role of fibrocystin in the development of the cystic dilations and portal fibrosis observed in Caroli syndrome.[16] In the liver, fibrocystin is a component of the cilia on the luminal side of cholangiocytes. Fibrocystin is an important receptor in the protein signaling pathways that regulate bile composition and the apoptotic processes of the biliary epithelium. Cilia detect mechanical, chemical, and osmotic stimuli, which in turn alter bile composition through complex intracellular signaling pathways. Additionally, fibrocystin is involved in the normal development of the liver and kidneys by regulating cell proliferation. A complete absence or significant abnormality of fibrocystin leads to structural damage to the liver parenchyma, resulting in gross cystic dilations and hepatic fibrosis characteristic of Caroli syndrome.[17][18][19][20]

Histopathology

On a microscopic level, Caroli disease is characterized by large bile ducts that are dilated with marked periductal inflammation and soft tissue protrusions into the dilated ducts. These dilations are in communication with the extrahepatic bile ducts. Sometimes, the involvement is confined to a single lobe, with the left lobe being more commonly affected. Histologically, the hepatic cysts demonstrate variable-sized cysts along the portal tract. In congenital hepatic fibrosis (Caroli syndrome), microscopic features include nodularity, extensive septa formation with enlarged portal tracts, and hypoplastic and fibrotic portal vein branches with abnormal branching angles.[2] 

History and Physical

Most patients with Caroli disease present with symptoms and are diagnosed before the age of 30. Symptoms arise from abnormal intrahepatic bile ducts, which lead to biliary stasis and sludge formation, causing obstruction of bile flow. The most common presentation includes the classic triad of cholangitis—fever, abdominal pain, and jaundice. Pruritus is also frequently reported due to hyperbilirubinemia from intrahepatic cholestasis. Hepatolithiasis is a common complication of Caroli disease, and in rare cases, stones can obstruct the pancreatic duct.

Although the incidence of pancreatitis in Caroli disease is low, there have been case reports of patients being diagnosed with Caroli disease after presenting with pancreatitis.[15][21] Some patients with Caroli disease may have advanced cystic dilations without a history of cholangitis or liver abscess formation. These patients might present with chronic, intermittent right upper quadrant pain without acute cholangitis.[8] 

The presentation of Caroli syndrome can vary, with symptoms appearing either early or later in adolescence. Due to its association with ARPKD, Caroli syndrome may be incidentally diagnosed in neonates presenting with oliguria and respiratory insufficiency.[22] Over time, recurrent cholangitis can lead to biliary cirrhosis and portal hypertension. Individuals aged 30 or older and with Caroli disease, or those with Caroli syndrome, may present with symptoms and signs of portal hypertension, such as splenomegaly, ascites, and variceal bleeding. Additionally, patients with Caroli disease or syndrome are at an increased risk for developing cholangiocarcinoma.[5]

The physical examination of a patient with Caroli disease or syndrome may reveal tenderness in the right upper quadrant, hepatomegaly due to gross enlargement from cystic disease, and splenomegaly due to portal hypertension. As hepatic fibrosis progresses, signs such as shifting dullness and fluid thrill, indicative of ascites, may be observed. Although rare, other signs of cirrhosis, including spider naevi, can also be present.

Evaluation

In Caroli disease, laboratory findings are often nonspecific. In the setting of biliary obstruction or cholangitis, transaminase levels may be elevated, and elevations in serum alkaline phosphatase and direct bilirubin are common.[5] However, unlike other biliary diseases such as primary sclerosing cholangitis, which typically presents with consistently elevated liver-associated enzymes, Caroli disease often has baseline transaminase levels that remain within the normal range.[3][6] Leukocytosis may be observed during cholangitis, while leukopenia and thrombocytopenia may occur if portal hypertension is present.

Various imaging modalities, including ultrasonography, computed tomography (CT), and MRCP, have important roles in evaluating Caroli disease.[2] Ultrasound is typically the initial imaging study due to its cost-effectiveness and limited radiation exposure. Intrahepatic saccular dilations, which may be focal or diffuse, can be visualized on both ultrasound and CT. Additionally, liver fibrosis, varices, and renal cysts can be detected on ultrasound and CT in patients with Caroli syndrome.

In patients with Caroli disease, imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) often reveals the portal triad as a small, enhanced dot within the dilated intrahepatic bile ducts. This imaging finding, known as the "central dot" sign, suggests Caroli disease. While initially considered pathognomonic for Caroli disease, the central dot sign can also be observed in cases of obstructive dilation.[3][23][24] 

MRCP is particularly useful for visualizing the entire biliary tract and liver, allowing for the assessment of disease extent and severity.[10] MRCP is also effective in detecting hepatolithiasis and diagnosing cholangiocarcinoma.[10] MRCP is preferred over endoscopic retrograde cholangiopancreatography (ERCP) for evaluation and diagnosis due to the latter's higher risk of precipitating cholangitis and pancreatitis, particularly with the use of contrast dye.[23] Liver biopsy is rarely used in the diagnostic evaluation of Caroli disease or syndrome but may be performed to document associated hepatic fibrosis if necessary. 

Treatment / Management

According to the clinical presentation, the mainstay of therapy for patients with Caroli disease is supportive and individualized. Cholangitis resulting from biliary obstruction is treated with antibiotics covering gram-negative and anaerobic rod-shaped bacteria. Adequate biliary drainage may be achieved through biliary stent placement using ERCP or via interventional radiology–guided percutaneous transhepatic catheter (PTC) placement. PTC is generally more effective for draining intrahepatic obstruction, and patients may require indwelling catheters with periodic flushing and changes. Ursodeoxycholic acid is used to manage severe cholestasis and is recommended for patients with Caroli disease or syndrome, even if asymptomatic.[5][25][26][27](A1)

Caroli syndrome is often complicated by portal hypertension, leading to sequelae such as splenomegaly, ascites, and variceal bleeding, which may present during adolescence. These complications should be managed in a traditional manner—endoscopic band ligation for variceal bleeding, nonselective beta blockers for prophylaxis, and diuretics for ascites.[10] Surgical intervention is recommended for patients who remain symptomatic despite conservative management.[6][28] Some authors have recommended segmentectomy, lobectomy, or hepaticojejunostomy, depending on the range of cystic formation, for the treatment of Caroli disease. Studies have shown excellent long-term outcomes with partial hepatectomy or lobectomy in patients with unilobar involvement of Caroli disease.[29][27](B2)

The prevalence of cholangiocarcinoma in Caroli disease and syndrome has been reported as approximately 7%.[30][31] Although general consensus does not exist on screening for cholangiocarcinoma, the European Association for the Study of the Liver guidelines recommend screening with MRCP every 12 months after diagnosis (a weak recommendation with 90% consensus based on available case reports and case-control studies). Monitoring serum tumor markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) is not recommended due to their poor diagnostic accuracy. However, case reports suggest that CA 19-9 may have the potential as a diagnostic marker in asymptomatic patients with polycystic liver disease and ADPKD.[32] (A1)

Liver transplantation is currently the only definitive treatment for Caroli syndrome. Referral for liver transplantation is recommended for patients with Caroli disease or syndrome who are symptomatic with recurrent cholangitis and have either bilobar involvement or monolobar involvement with liver fibrosis or portal hypertension, especially when hepatectomy is not feasible.[33][28][25](A1)

Differential Diagnosis

The differential diagnoses based on clinical presentation include acute cholecystitis, ascending cholangitis, and recurrent pyogenic cholangitis. On imaging, saccular dilations may resemble choledochal cysts seen in autosomal dominant polycystic liver disease, hepatic abscesses, and primary sclerosing cholangitis. MRCP helps distinguish the intrahepatic large duct dilation characteristic of Caroli disease from obstructive bile duct dilation and polycystic liver disease. 

Prognosis

The prognosis of Caroli disease varies based on the extent of intrahepatic bile duct dilation and liver involvement. While the condition can often be managed conservatively, individuals with diffuse lobar involvement, recurrent cholangitis, and biliary cirrhosis are at increased risk of morbidity and mortality.

Symptomatic individuals with monolobar involvement generally have good outcomes with partial hepatectomy. However, individuals with multilobar or diffuse liver involvement tend to have poor outcomes with liver resection, making liver transplantation the only definitive treatment.[28][25]

Complications

The most common complication of Caroli disease is recurrent bacterial cholangitis, caused by bile stasis and the formation of intrahepatic calculi. These infections can lead to liver abscesses and sepsis if not promptly treated.[34] Additionally, patients with Caroli disease are at an increased risk of developing cholangiocarcinoma due to chronic inflammation and cellular changes in the bile ducts. Other potential complications include portal hypertension, especially in cases of Caroli syndrome, and hepatic fibrosis, which can progress to cirrhosis and liver failure.