Related Terms

• Autosomal dominant inheritance, autosomal recessive inheritance, Caroli disease, Caroli syndrome, complex Caroli disease, congenital dilatation of intrahepatic bile duct, fibrocystin, isolated Caroli disease, PKHD1, polycystic kidney disease, polyductin, simple Caroli disease.

Background

• Caroli disease is a rare genetic disorder that affects the bile ducts, which carry bile from the liver to aid in the digestion of fats. Researchers have identified two forms of Caroli disease. The isolated, or simple, form is characterized by a widening of the bile ducts. The complex form, which is also referred to as Caroli syndrome, is similarly characterized by a widening of the bile ducts, but malformations of the smaller bile ducts, congenital hepatic fibrosis (scarring of liver tissue), high blood pressure, and kidney problems are also present. The differences in the causes for the two forms have not yet been discovered. For the purposes of this article, the isolated form of Caroli disease will be referred to simply as Caroli disease, while the more severe form will be referred to as Caroli syndrome.

• The exact genetic mutation causing Caroli disease and Caroli syndrome is not known. However, some individuals with Caroli syndrome may have a mutation in the PKHD1 gene. PKHD1 is found primarily in the kidneys, with lower levels in the liver, pancreas, and lungs. The PKHD1 gene encodes for a protein called fibrocystin, which is a receptor-like protein thought to be involved in tubulogenesis and bile duct maintenance. A mutation in this gene is also thought to cause autosomal recessive polycystic kidney disease.

• The simple form of Caroli disease is inherited, or passed down among family members, as an autosomal dominant trait. It may also occur in individuals with no family history of the disorder as the result of a spontaneous genetic mutation in the egg or sperm cells or in the developing embryo. The complex form, Caroli syndrome, is inherited as an autosomal recessive trait.

• Caroli disease and Caroli syndrome are very rare, affecting about 1 in 1,000,000 people. Caroli syndrome is more common than Caroli disease, although it is unclear to what degree. Symptoms appear first in adults, although childhood and neonatal cases have been reported. There is no cure for Caroli syndrome or disease. Treatment involves managing symptoms. Mortality in Caroli disease is caused by complications. After cholangitis (inflammation of the bile duct) occurs, which it does in both the disease and the syndrome, a large number of patients die within 5-10 years. The average age of patients at diagnosis is 22 years. Both conditions are more common in females than in males.

Risk Factors

• Caroli disease and Caroli syndrome are inherited conditions. Therefore, the only known risk factor is a family history of these conditions. There is a lack of evidence demonstrating that these conditions particularly affect any race or ethnic group. The chances of inheriting either form of the disease with a family history are unknown at present. Genetic conditions may be influenced by environmental factors.

Causes

• Genetic mutations: The exact genetic mutations that cause Caroli disease and Caroli syndrome are not known. Researchers have found that people with Caroli syndrome may have mutations in the PKHD1 gene. However, the exact prevalence of this mutation is unknown. The PKHD1 gene is found primarily in the kidneys, with lower levels in the liver, pancreas, and lungs. The PKHD1 gene encodes for a protein called fibrocystin, which is a receptor-like protein thought to be involved in tubulogenesis (the formation of tubules in epithelial or endothelial cells) and bile duct maintenance. This gene has also been linked to autosomal recessive polycystic kidney disease, which is the most common form of inherited kidney disease in young people and which has been found in some people with Caroli syndrome.

• Autosomal dominant inheritance: Caroli disease, or the simple form of the disease, is believed to be inherited as an autosomal dominant trait. Individuals receive two copies of most genes, one from the mother and one from the father. For a dominant disorder to occur, only one defective copy of the gene is necessary. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.

• Autosomal recessive inheritance: Caroli syndrome, which is the complex form of the disease, is believed to be inherited as an autosomal recessive trait, meaning that an individual must inherit two copies of the defective gene, one from each parent. Individuals who inherit only one copy of the defective gene generally have no symptoms and are called carriers, because they can pass on the disorder to their children.

• If one parent is a carrier, then each child has a 50% chance of inheriting one defective gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of inheriting neither defective gene. Therefore, if both parents are carriers, about one out of four children will have Caroli syndrome.

• Caroli disease and Caroli syndrome are very rare, affecting about 1 in 1,000,000 people. Caroli syndrome is more common than Caroli disease.

• Random occurrence: Caroli disease sometimes occurs in individuals with no family history of the disorder. This is the result of a spontaneous genetic mutation in the egg or sperm cells or in the developing embryo. There is a lack of evidence showing that Caroli syndrome can occur through spontaneous mutation.

Signs and Symptoms

• General: Symptoms of Caroli disease and Caroli syndrome generally emerge in adulthood, although there have been reports of symptoms in children and young infants. The first symptoms typically include fever, intermittent abdominal pain, and an enlarged liver. Jaundice may occur.

• Congenital hepatic fibrosis: Individuals with Caroli syndrome may experience congenital hepatic fibrosis, the scarring of liver tissue that may lead to portal hypertension, which occurs when scar tissue blocks the flow of blood through the liver.

• Pain: People with Caroli disease or Caroli syndrome may experience localized pain from cysts, which are closed sacs that may contain air, fluids, or semisolid material that may clear up on their own or have to be surgically removed. Individuals with either form of the disease can develop cysts in the kidneys and enlargement of the liver and spleen, and they may also have abdominal pain.

• Portal hypertension: High blood pressure may develop in the portal vein, which carries blood from the digestive system to the liver. The most common cause of this (called portal hypertension) is cirrhosis, which results from scarring of the liver. This scar tissue blocks the flow of blood through the liver. An enlargement of the liver or spleen may occur as a result of this condition.

• Polycystic kidney disease: Although rare, polycystic kidney disease has occurred in individuals with Caroli syndrome. Polycystic kidney disease is associated with growths of numerous cysts in the kidneys. These cysts can profoundly enlarge the kidneys while replacing much of their normal structure, resulting in reduced kidney function and leading to kidney failure.

• Widening of the bile ducts: Caroli disease and Caroli syndrome are associated with a nonobstructive dilation of the bile ducts. This may cause recurrent bacterial cholangitis, which is a bacterial infection that occurs during inflammation of the bile duct.

Types of the Disease

• Caroli disease: Caroli disease, also known as isolated or simple Caroli disease, is the milder and less common of the two forms of the condition. Caroli disease is characterized by a widening of the larger bile ducts. This form of the disease is inherited, or passed down among family members, as an autosomal dominant trait.

• Caroli syndrome: Caroli syndrome, or complex Caroli disease, is the more severe and common form of the condition. In addition to widening of the small bile ducts, Caroli syndrome is associated with high blood pressure, kidney problems, including polycystic kidney disease, and occasionally liver disease. This form of the disease is inherited as an autosomal recessive trait.

Diagnosis

• Biopsy: In a biopsy, a small sample of tissue is removed from the body and evaluated in a lab. To help diagnose Caroli disease or Caroli syndrome, a biopsy of the liver may be done to determine the presence and extent of bile duct abnormalities. Bile ducts carry bile from the liver to aid in the digestion of fats. In addition, the presence of cholangitis can be confirmed following examination of the tissue.

• Imaging studies: Ultrasound, a noninvasive procedure that uses sound waves to create a moving picture of internal organs, can be used to determine the extent of bile duct dilation. Magnetic resonance imaging (MRI), which uses magnets to create an image of internal organs, can be used to visualize the liver, kidney, and bile ducts in order to examine the extent of inflammation and the presence of cysts. Percutaneous transhepatic cholangiography is an X-ray test that can help show whether there is a blockage in the liver or the bile ducts that drain it. Endoscopic retrograde cholangiopancreatography is an X-ray combined with an endoscope (a long, flexible lighted tube). Through the endoscope, the physician can see the stomach, duodenum, and ducts in the biliary tree and pancreas. These techniques can help create an image of the bile ducts and determine the extent to which they are inflamed. While these techniques may be helpful, they are invasive and may cause complications.

• Lab studies: Blood tests may reveal abnormal levels of white blood cells, which may indicate bacterial cholangitis, a bacterial infection that occurs during inflammation of the bile duct. Lab tests may also be used to test liver function, as evidenced by prothrombin activity, bilirubin, and albumin. Caroli disease and Caroli syndrome may affect kidney function. The blood urea nitrogen (BUN) test is a test of kidney function and can be used in individuals with Caroli disease and Caroli syndrome to assess kidney function. Urea is a byproduct of protein metabolism. This waste product is formed in the liver, then filtered from the blood and excreted in the urine by the kidneys. The BUN test measures the amount of nitrogen contained in the urea. High BUN levels can indicate kidney dysfunction, but because blood urea nitrogen is also affected by protein intake and liver function, the test is usually done in conjunction with a blood creatinine test, a more specific indicator of kidney function. This test measures blood levels of creatinine, a by-product of muscle energy metabolism that, like urea, is filtered from the blood by the kidneys and excreted into the urine. Production of creatinine depends on an individual's muscle mass, which usually fluctuates very little. With normal kidney function, the amount of creatinine in the blood remains relatively constant. For this reason, and because creatinine is affected very little by liver function, elevated blood creatinine is a more sensitive indicator of impaired kidney function than elevated urea nitrogen.

• Physical exam: A complete physical exam should check for enlargement of the liver and spleen, and tenderness in the right upper portion of the abdomen. Patient interview questions should probe for a history of abdominal pain and a family history of kidney disease. Jaundice may be present.

• Genetic testing: Deoxyribonucleic acid (DNA) testing may be available for Caroli syndrome, the complex, recessive form of the disorder, because it has been linked to a mutation in the PKHD1 gene. This test cannot be definitive for the condition, because this gene has also been linked to autosomal recessive polycystic kidney disease.

Complications

• Bile duct cancer: People with Caroli syndrome, the complex form of the disorder, are about 100 times more likely than the general population to develop cholangiocarcinoma, cancer of the bile ducts, which carry bile from the liver to aid in the digestion of fats. Cholangiocarcinoma is considered an incurable and rapidly lethal disease. Surgery is needed to remove the tumors. However, it is more often the case that the disease has progressed too far for surgery to be effective by the time it is discovered.

• Bile duct infection: Cholangitis, a bacterial infection of the bile ducts, is a common complication of Caroli disease and Caroli syndrome. Cholangitis may cause severe pain in the upper right-hand portion of the abdomen. If left untreated, cholangitis may become severe enough to be life-threatening.

• Gallstones: Abnormal bile duct function may also lead to gallstones, which are painful blockages of the gallbladder. When gallstones cause symptoms, they may cause intense pain in the upper abdominal area and back pain between the shoulder blades or under the right shoulder. Nausea and vomiting may occur.

• Kidney failure: Progressive cysts are closed sacs that may contain air, fluids, or semisolid material that may resolve on their own or have to be surgically removed. These cysts progressively destroy the healthy kidney tissue and may lead to decreased kidney function and kidney failure. People who show signs of Caroli syndrome early in life are more likely to sustain kidney damage from the condition. Symptoms of kidney failure include an inability to regulate water and electrolyte balances, to clear waste products from the body, or to promote red blood cell production. Symptoms also include fatigue, weakness, shortness of breath, and generalized swelling, eventually leading to multiple organ failure and death.

• Liver failure: People with Caroli syndrome are prone to the growth of fibrous tissue in the liver, which can cause progressive damage, cirrhosis (scarring of the liver to the point where scar tissue replaces healthy tissue), and eventually total liver failure. A damaged liver cannot remove toxins from the body, causing them to accumulate in the body and brain. In addition, loss of liver function can lead to liver cancer, which cannot be reversed.

• Variceal bleeding: Portal hypertension (increased blood pressure in the portal vein, which carries blood from the digestive system to the liver) can cause blood vessels to become extended and vulnerable to injury and bleeding. Variceal bleeding is bleeding from dilated blood vessels in the esophagus or stomach that can cause profound blood loss and may lead to anemia (a blood disorder that occurs when levels of red blood cells become too low).

• Other: There have been reports of people with Caroli syndrome who have experienced an aneurysm, which is when a blood vessel produces a balloon-like bulge that can burst and result in death.

Treatment

• General: There is no cure for Caroli disease or Caroli syndrome. Instead, treatment aims to reduce symptoms and prevent complications. Symptoms appear first in adults, although childhood and neonatal cases have been reported. Mortality in Caroli disease is caused by complications. After cholangitis (inflammation of the bile duct) occurs, which it does in both the disease and syndrome states, a large number of patients die within 5-10 years. The average age of patients at diagnosis is 22 years.

• Antibiotics: Antibiotics such as ampicillin and sulbactam may be prescribed to treat cholangitis, an infection of the bile duct.

• Dialysis: When the kidneys begin to fail, patients can undergo several types of dialysis to restore the filtering function of the kidneys. In hemodialysis, a patient's blood is circulated into an external filter and cleaned. The filtered blood is then returned to the body. In peritoneal dialysis, a fluid containing dextrose is introduced into the abdomen through a tube. This solution absorbs the wastes in the body and is then removed.

• Kidney transplantation: Some patients who experience kidney failure may undergo kidney transplantation. Kidneys that are transplanted into patients with Caroli syndrome do not develop cysts, which are closed sacs that may contain air, fluids, or semisolid material that may resolve on their own or may have to be surgically removed. However, transplantation is associated with complications, including infection and the possibility of rejection of the new organ. To reduce the chance of rejection, patients may need to take immunosuppressant drugs.

• Liver transplantation: Some patients who experience liver failure may undergo liver transplantation. Livers that are transplanted into patients with Caroli syndrome do not tend to become fibrotic, or hardened. However, transplantation is associated with complications, including infection and the possibility of rejection of the new organ. To reduce the chance of rejection, patients may need to take immunosuppressant drugs.

• Surgery: Some patients with Caroli disease benefit from surgical draining of the affected bile ducts, which carry bile from the liver to aid in the digestion of fats. In more severe cases, however, this procedure may be inadequate. In some patients who experience severe pain, surgery may be performed to reduce the size of the cysts growing on the kidneys. This surgery does not provide a cure for the condition, as the cysts grow back. Additionally, surgery may be used to remove portions of the liver in some people with liver fibrosis who are not candidates for transplantation. Surgery may also be an option for the treatment of bile duct infections that do not respond to antibiotic treatment.

• People with Caroli syndrome, the complex form of the disorder, are about 100 times more likely than the general population to develop cholangiocarcinoma (cancer of the bile ducts), which carry bile from the liver to aid in the digestion of fats. Cholangiocarcinoma is considered an incurable and rapidly lethal disease. Surgery is needed to remove the tumors. However, it is more often the case that the disease has progressed too far for surgery to be effective by the time it is discovered.

• Ursodiol: Ursodiol (e.g., Urso®, Actigall®) is a bile acid and may be prescribed to dissolve gallstones. Side effects of these medications include diarrhea, severe stomach pains, nausea, and vomiting. Ursodiol must be used for one or more years, and the gallstones will return within five years in 50% of patients who have had successful dissolution of their gallstones.

Integrative Therapies

• Currently there is a lack of scientific evidence on the use of integrative therapies for the treatment or prevention of Caroli disease and Caroli syndrome.

Prevention

• Caroli disease and Caroli syndrome are rare inherited disorders. Therefore, there are no known means of preventing these conditions. Because the exact genetic mutations causing these conditions have not yet been identified, genetic testing, including prenatal diagnostic procedures, are currently unavailable.

• There have been reports of prenatal diagnosis using ultrasound. Abnormalities in the bile ducts and kidneys can be examined using ultrasound technology, which allows for a visualization of the fetus and its organs while in the womb.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

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Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

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