Type 1

PFIC (Progressive Familial Intrahepatic Cholestasis) Type 1 is characterized by a mutation in FIC-1, a gene predicted to encode a P-type ATPase that may be involved in phospholipid translocation. It was previously identified as a clinical entity known as Byler’s disease. Patients with PFIC may have severe cholestasis manifest by intense pruritus, fat malabsorption and fat soluble vitamin deficiencies. PFIC-1 may be associated with extrahepatic manifestations, especially after liver transplantation, since the FIC-1 gene is expressed in many tissues other than the liver.

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Type 2

PFIC (Progressive Familial Intrahepatic Cholestasis) Type 2 is caused by mutations in the gene that codes for the bile salt export pump, or BSEP. Hepatic excretion of bile acids is primarily controlled by BSEP, so severe cholestasis is common in patients with BSEP disease. As BSEP is expressed only in the liver, extrahepatic disease in PFIC-2 is secondary rather than primary.

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Type 3

PFIC (Progressive Familial Intrahepatic Cholestasis) Type 3 is caused by mutations in the MDR3 gene, a flippase that moves phospholipid to the outer leaflet of cell membranes permitting biliary exctretion. Without functional MDR3, bile is deficient in phosphatidylcholine and abnormally caustic. This damages hepatocytes and bile ducts. The abnormal bile also is prone to form gallstones.

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Type 4

PFIC (Progressive Familial Intrahepatic Cholestasis) Type 4 is a mutation in the TJP2 protein. The TJP2 protein (Tight Junction Protein 2, sometimes called ZO2) plays a role in structures called ‘tight junctions.’ Tight junctions occur where cells meet, and help to control what molecules are able to pass between cells, as well as separating different parts of the cell membrane from each other. Such junctions are important throughout the body, and TJP2 is expressed in many different tissues.

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Type 5

PFIC (Progressive Familial Intrahepatic Cholestasis) Type 5 is caused by mutation in NR1H4, which encodes the FXR (the Farnesoid X Receptor) protein. The FXR protein is known as a nuclear receptor and transcription factor. This means it plays an important role in controlling the expression of genes. FXR is important in regulation of bile acid metabolism in the liver and intestine, as well as in other aspects of metabolism. Patients with PFIC due to FXR deficiency seem to develop rapidly progressing liver disease very early in infancy

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MYO5B (no PFIC number in use)

MYO5B is expressed in multiple parts of the body, and is involved in maintaining proper functioning of cell membranes and helping to move proteins, such as BSEP, to where they are needed in the cell membrane. Some patients with cholestasis due to MYO5B deficiency have progressive liver disease, while others have it only intermittently. Even in the patients with progressive liver disease, progression usually seems slower than in patients with other genetic forms of PFIC.

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