Progressive familial intrahepatic cholestasis: MedlinePlus Genetics

Description

Progressive familial intrahepatic cholestasis (PFIC) is a broad term for a group of disorders that cause liver disease that worsens over time. Cholestasis is a condition that impairs the release of a digestive fluid called bile, which is made and released by the liver. In people with cholestasis, bile builds up in the liver, impairing its function and causing liver damage. Because the problems with bile release occur within the liver, the condition is described as intrahepatic.

The signs and symptoms of PFIC can vary, but they typically begin in infancy or early childhood. Itching (pruritus) is a characteristic feature of PFIC and may be severe enough to significantly impact a person’s quality of life. Additional signs and symptoms of PFIC often include yellowing of the skin and the whites of the eyes (jaundice), an inability to gain weight and grow at the expected rate (faltering weight), and urine that is darker than usual. Progressive liver damage can lead to high blood pressure in the vein that supplies blood to the liver (portal hypertension), an enlarged liver and spleen (hepatosplenomegaly), and scarring of the liver (cirrhosis). Many people with PFIC eventually develop liver failure and require a liver transplant.

Researchers have discovered more than 10 types of PFIC, each with a different genetic cause. The most common types are:

FIC1 deficiency (formerly known as PFIC1)
BSEP deficiency (formerly known as PFIC2)
MDR3 deficiency (formerly known as PFIC3)

The signs and symptoms of FIC1 deficiency typically begin in infancy and can range from mild to severe. In addition to the features listed above, people with FIC1 deficiency may have short stature, hearing loss, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. People with severe FIC1 deficiency may not survive past childhood. Those with mild to moderate FIC1 deficiency may have episodes of cholestasis, jaundice, and severe itching followed by intervals without signs and symptoms. In these individuals, liver disease may not develop until later in life, if at all. Mild to moderate FIC1 deficiency is sometimes called benign recurrent intrahepatic cholestasis type 1 or BRIC1.

BSEP deficiency is the most common type of PFIC. The signs and symptoms of BSEP deficiency typically begin in infancy and can be severe. People with BSEP deficiency often develop liver failure before reaching adulthood. Additionally, affected individuals are at increased risk of developing certain cancers, including a type of liver cancer called hepatocellular carcinoma (HCC). Mild BSEP deficiency is sometimes called benign recurrent intrahepatic cholestasis type 2 or BRIC2.

The signs and symptoms of MDR3 deficiency may begin in early childhood or may not appear until after the age of 2 or 3 years. Some people with MDR3 deficiency develop liver failure. In these people, liver failure can occur in childhood or adulthood. Affected individuals have an increased risk of developing problems that involve the network of tubes that connect the liver, gallbladder, and small intestine (bile ducts). These problems can include gallstones and a type of cancer called cholangiocarcinoma (CCA).

Frequency

PFIC is estimated to affect 1 in 50,000 to 100,000 people.

Causes

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in more than 10 different genes can cause PFIC. Pathogenic variants in the ATP8B1, ABCB11, and ABCB4 genes cause the three most common forms of PFIC.

Many of the genes that are associated with PFIC provide instructions for producing proteins that help move a particular component of bile, called bile acids, in and out of the liver. Bile acids help break down fats from food so that they can be absorbed by the intestines.

Pathogenic variants in the ATP8B1 gene cause FIC1 deficiency. The ATP8B1 gene provides instructions for making a protein that helps protect liver cells from the damaging effects of bile acids as they are moved out of the liver. The pathogenic variants in the ATP8B1 gene that cause FIC1 deficiency likely alter the makeup of the liver cell membrane, impairing the membrane's ability to transport bile acids. However, it is not clear exactly how these variants cause the cholestasis and liver damage seen in people with FIC1 deficiency.

Pathogenic variants in the ABCB11 gene cause BSEP deficiency. The ABCB11 gene provides instructions for making a protein called the bile salt export pump (BSEP). This protein is found in the liver, and its main role is to move bile acids out of liver cells. Pathogenic variants in the ABCB11 gene can result in a buildup of bile acids, which damages liver cells and causes liver disease.

Pathogenic variants in the ABCB4 gene cause MDR3 deficiency. These variants reduce the number of molecules called phospholipids that are available to bind to bile acids. These phospholipids act as a buffer. Large amounts of free (unbuffered) bile acids are potentially harmful to cells. However, when bile acids are bound to phospholipids, they are less toxic. When fewer phospholipids are available to bind to bile acids, bile acids can build up and cause liver damage.

Some people with PFIC do not have an identified pathogenic variant in the genes that are currently associated with PFIC. In these cases, the cause of the condition is unknown.

Inheritance

PFIC is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. Usually, the parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Some adults with only one pathogenic variant in a gene that causes PFIC may be at increased risk for developing various conditions, including gallstones, a liver disorder that typically occurs during the second half of pregnancy (intrahepatic cholestasis of pregnancy or ICP), drug-induced cholestasis, or a temporary form of cholestasis that occurs in infants (transient neonatal cholestasis).

Other Names for This Condition

PFIC

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Clinical Trials

ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

PubMed

References

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Progressive familial intrahepatic cholestasis