What are the other Names for this Condition? (Also known as/Synonyms)

• Congenital Dilatation of the Intrahepatic Bile Duct

What is Caroli Disease? (Definition/Background Information)

• Caroli Disease is a rare genetic disorder characterized by the widening of the intrahepatic bile ducts, which are the ducts that carry bile away from the liver
• There are two forms of Caroli Disease:
  • The simple form is characterized by dilatation of the bile ducts 
  • The second, more complex form, is referred to as Caroli Syndrome, which is often a combination of Caroli Disease and congenital hepatic fibrosis
• Caroli Syndrome is associated with fibrous tissue in the liver (congenital hepatic fibrosis) and high blood pressure in the portal artery (portal hypertension). Polycystic kidney disease is often associated with Caroli Syndrome, and in severe cases, it can lead to liver failure
• Caroli Disease is much less common than the more complex form, Caroli Syndrome; nevertheless, both are more common in women than men. The cause of the development of this condition is not well understood
• Treatment options depend on the type of signs and symptoms experienced by the individual and the severity of the disease. However, despite treatment, the prognosis of Caroli Disease is typically unfavorable

Who gets Caroli Disease? (Age and Sex Distribution)

• Caroli Disease is observed chiefly in Asia, and individuals are often diagnosed under 22. It is much less common than its more severe, complex form, Caroli Syndrome
• Caroli Disease commonly manifests during adulthood, although in some cases, symptoms can be seen as early as birth
• It is more common in women than men
• Worldwide, individuals of all races and ethnic groups may be affected

What are the Risk Factors for Caroli Disease? (Predisposing Factors)

• In a vast majority of individuals, there are no identified risk factors for Caroli Disease
• In some individuals, a positive family history is the only known risk factor for the condition
• Cholangiocarcinoma, a type of cancer that arises from the cells within the bile ducts, may be a risk factor

It is important to note that having a risk factor does not mean one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Caroli Disease? (Etiology)

Caroli Disease is a congenital (present from birth) disorder characterized by the abnormal development of the bile duct in the liver during fetal development. However, the exact cause of the formation of this disorder is unknown.

• Caroli Disease (isolated form) is thought to arise from a sporadic mutation that occurs for unknown reasons. Researchers hypothesize that it is transmitted as an autosomal dominant trait
• In comparison, the more complex form of this disease appears to be transmitted as an autosomal recessive trait, i.e., Caroli Syndrome is reportedly autosomal recessive
• The gene responsible for the mutation has been traced to chromosome 6 (6p21.1-p12). Chromosome 6p21.1-p12 refers to band regions 12 and 21.1 on the short arm of chromosome 6. The bands localize the thousands of genes that are found on each chromosome
• Caroli Syndrome is characterized by multiple dilatations of intrahepatic ducts, often associated with congenital hepatic fibrosis (scarring of liver tissue)

Autosomal dominant: Autosomal dominant conditions are traits or disorders present when only one copy of the mutation is inherited on a non-sex chromosome. In these conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly functioning gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition, or pass it on to their offspring.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

• Research also shows a relationship between Caroli Disease and autosomal recessive polycystic kidney disease (ARPKD). Therefore, it is important to evaluate for a family history of kidney and liver disease
• Individuals with Caroli Syndrome have been found with a mutated PKHD1 gene, which is the gene that is associated with ARPKD. This specific gene is expressed mainly in the kidneys, with lower levels in the liver, pancreas, and lungs

What are the Signs and Symptoms of Caroli Disease?

Caroli Disease:

• The signs and symptoms of the simple form of Caroli Disease include frequent recurrent inflammation of the bile ducts of the liver
• Pus accumulation (abscess), stones in the bile ducts (intraductal lithiasis), fever, and abdominal pain are common symptoms of Caroli Disease
• There is an increased risk for the formation of gallstones
• In extreme cases, yellowing of the skin, mucous membranes, and whites of the eye (jaundice), and enlargement of the liver (hepatomegaly) may develop

Caroli Syndrome:

• The second, more complex form of Caroli Disease, Caroli Syndrome, is associated with irregular bands of fibrous tissue in the liver (congenital hepatic fibrosis). It affects the portal area of the liver, which is where the portal vein (carries blood from the stomach, intestine, and spleen to the liver) and the hepatic artery (carries blood from the aorta) enter the liver
• This particular form also presents with increased blood pressure of the portal vein (portal hypertension) and liver abscess
• It can also result in polycystic kidney disease and liver failure

Additionally, individuals with Caroli Disease are about 100 times more susceptible to developing certain benign or malignant tumors (such as cholangiocarcinoma).

How is Caroli Disease Diagnosed?

The diagnosis of Caroli Disease may involve the following tests and procedures:

• Complete physical evaluation and medical history assessment
• A diagnosis of Caroli Disease involves palpation and use of hands to examine the stomach and abdomen region
• Abnormal enlargement of the spleen and liver (splenomegaly and hepatomegaly, respectively), along with recurrent stomach pain, may prompt a physician to request imaging studies of the abdomen (such as an ultrasound or CT scan). The results of such studies may lead to a diagnosis of Caroli Disease
• Laboratory findings for Caroli Disease are generally non-specific. The following lab tests may be undertaken:
  • Complete blood count (CBC) test
  • Liver function and kidney function tests
• Radiological imaging studies may include:
  • Ultrasound and CT scan of the abdomen
  • Magnetic resonance cholangiopancreatography (MRCP)
  • Endoscopic retrograde cholangiopancreatography (ERCP)
• Cholangiography: Imaging of the bile duct completed by X-rays is the most accurate and final approach to show enlarged bile ducts resulting from Caroli Disease
• Tissue biopsy of the liver and evaluation of the specimen by a pathologist under the microscope

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Caroli Disease?

Caroli Disease can lead to an increased incidence of disease morbidity. The following complications may arise:

• Kidney damage is observed in 60% of the individuals; this can result in kidney failure
• Recurrent cholangitis, which is the inflammation of the bile duct system, usually with a superimposed bacterial infection
• Sepsis: A life-threatening condition that occurs when the body responds to the infection and injures its organs and tissues
• Choledocholithiasis: Gallstones that are present in the common bile duct
• Hepatolithiasis: The presence of stones (calculi) within the intrahepatic bile ducts (ducts that carry bile within the liver)
• Cholangiocarcinoma: Bile duct cancer composed of mutated epithelial cells
• Hepatic (liver) abscess
• Development of portal hypertension
• Portal hypertension can cause other illnesses, including splenomegaly (enlargement of the spleen), hematemesis (vomiting of blood), and melena (black or tarry stools)
• Esophageal varices that can cause vomiting and bleeding (excessive cough with a lot of bleeding)

How is Caroli Disease Treated?

The treatment of Caroli Disease depends on the signs and symptoms and the location of the abnormality.

• If the disease is limited to one lobe of the liver, a surgical resection of the liver (lobectomy) relieves symptoms and risk of death
• Antibiotics may be given to treat infection of the bile duct, and ursodiol (ursodeoxycholic acid) is typically administered to treat cholelithiasis. Abscess drainage may be performed if necessary
• Treatment of portal hypertension may be undertaken
• Liver transplantation is also an option where antibiotics have no effect and cholangitis is recurring. This also prevents cholangiocarcinoma from occurring in the future
• Liver transplantation is the only curative treatment for Caroli Disease and Caroli Syndrome
• Renal status should also be monitored in case of associated renal disease, which will help decide whether to perform a renal and liver transplant together

Regular medical screening at periodic intervals with tests and physical examinations is necessary and highly recommended.

How can Caroli Disease be Prevented?

Caroli Disease may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. Most cases are sporadic occurrences, meaning there is no family history of the condition.

In some rare cases, the condition may be familial, meaning they occur within families. In expecting parents with a prior history of Caroli Disease:

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Caroli Disease? (Outcomes/Resolutions)

The prognosis of Caroli Disease is dependent upon the severity of the signs and symptoms and associated complications, if any. It may be assessed on a case-by-case basis, but it is generally difficult to predict the long-term outlook that is primarily unfavorable.

• Death usually results from the complications of Caroli Disease rather than from the disease itself
• Following severe and recurring cholangitis (the most common complication), many patients die within 5-10 years
• Deaths are typically related to either liver failure or complications of portal hypertension

Additional and Relevant Useful Information for Caroli Disease:

The following resources link can help provide some useful information on cholangitis:

https://www.dovemed.com/diseases-conditions/cholangitis/