Types and Subtypes

Types and Subtypes of Progressive Familial Intrahepatic Cholestasis (PFIC)

This page gives more detail about the different subtypes of PFIC. More general information about PFIC can be found here, info about diagnosis and treatment is here, and info about the genetics of PFIC is here.

Note: You may see PFIC listed by number (1, 2, 3, etc.) or by it’s specific defective gene. It’s important to understand that before any of these genes were identified, PFIC was all lumped together as low ggt and high ggt PFIC. As specific genetic etiologies were identified they started to become numbers. PFIC 1 2 and 3 were the first 3 identified and those terms stuck. As research progresses and we identify many more genetic causes of PFIC, the numbering system may do away.

Summary

The subtypes of PFIC involve mutations in different genes; those mutations can be more or less severe which leads to variability in the disease even amongst the same gene. A gene is a piece of code that provides the recipe to make a specific protein. Proteins have important functions in the body, and mutations often result in deficiency or other malfunction of the coded proteins. The different subtypes of PFIC involve mutations of different genes, and therefore different proteins. The proteins have in common that they all have functions related to bile transport from the liver to the small intestine and back. Deficiencies of these proteins cause bile build-up in the liver (“cholestasis”).

More Common Types of PFIC

This subtype was previously known as Byler’s disease. It is characterized by mutations in the ATP8B1 gene, which cause deficiency of the FIC1 protein. Deficiency of the FIC1 protein can lead to Benign Recurrent Intrahepatic Cholestasis (BRIC1) as well as PFIC1. These two are now considered different levels of severity of the same condition.

It is not clear yet why exactly deficiency of the FIC1 protein causes build-up of bile in liver cells, and other symptoms of BRIC1 or PFIC1.

Characteristics and Symptoms of FIC 1

  • Jaundice in the first months of life
  • Severe itch (pruritus) beginning in the first year of life
  • High levels of serum bile acids, low GGT levels
  • Fat-soluble vitamin deficiencies are common (may require testing to identify)
  • Progresses to chronic liver disease and possible cirrhosis at varying rates
  • Potential problems that are independent of the liver including hearing problems, irritation of the pancreas, chronic diarrhea, growth issues and chronic cough

Characteristics and Symptoms of BRIC1

  • Recurrent episodes of symptoms which may be quite mild
  • First sign is often pruritus, but jaundice may also occur
  • The time of a first episode varies widely (records show 2 months to 47 years)
  • The first episode may be precipitated by factors such as infection or medication
  • Frequency, duration, and severity of episodes can vary greatly
  • Episodes often reduce with age
  • In some cases BRIC evolves to be like PFIC1 (i.e. there are no periods of remission of the symptoms) and can progress to chronic liver disease

Mutations in the ABCB11 gene are responsible for the deficiency of the Bile Salt Export Pump (BSEP) protein. This protein works like a pump and moves bile salts out of liver cells. The deficiency of this protein directly leads to build-up of bile in liver cells, which in turn causes liver damage. Depending on the severity of the mutation, the BSEP protein is reduced or completely absent.

Characteristics and Symptoms of BSEP deficiency

  • GGT levels are normal (see more information on GGT tests here)
  • Pruritus (itch) becomes severe in the first years of life
  • Cirrhosis (liver scarring) often occurs before the age of 10 years
  • Milder intermittent forms (sometimes called BRIC 2) have also been identified
  • There is a high risk of liver cancer in some individuals this type of PFIC which makes regular monitoring by blood test and ultrasound particularly important

Deficiency in both either the FIC1 protein or the BSEP protein can lead to a more milder form of PFIC called BRIC. BRIC stands for Benign Recurrent Intrahepatic Cholestasis, and depending on the protein involved can take on those symptoms of its PFIC form.

Characteristics and Symptoms of BRIC1 and 2

    • Recurrent episodes of symptoms which may be quite mild
    • First sign is often pruritus, but jaundice may also occur
    • The time of a first episode varies widely (records show 2 months to 47 years)
    • The first episode may be precipitated by factors such as infection or medication
    • Frequency, duration, and severity of episodes can vary greatly
    • Episodes often reduce with age
    • In some cases BRIC evolves to be like PFIC 1 or 2 (i.e. there are no periods of remission of the symptoms) and can progress to chronic liver disease

Mutations in the ABCB4 gene cause deficiency of the MDR3 protein. This protein seems to be involved in transporting of phospholipids (a type of fat) from liver cells into bile, where they bind to bile acids. Deficiency of this protein causes a lack of fats for bile acid to bind, which in turn causes injury to the tubes that drain bile from the liver. This can then lead to liver injury.

Characteristics and Symptoms of MDR3 deficiency (PFIC 3)

  • High levels of GGT in the blood — this is an important difference from FIC1 and BSEP deficiencies
  • Pruritus tends to be milder
  • Bile duct damage may occur
  • Gallstones and stones within the liver are common
  • There is a very wide range of severity
  • PFIC 3 can occur during infancy, childhood and even into young adulthood – when it presents in childhood and young adulthood it may be with cirrhosis, an enlarged spleen or low platelets
  • During pregnancy, women who are carriers for this disease can develop jaundice and itching

The following three types have been found more recently:

The TJP2 protein (Tight Junction Protein 2, sometimes called ZO2) plays a role in “tight junctions”. Tight junctions are areas where the membranes of two adjacent cells join to form a barrier. The barrier controls what molecules are able to pass between cells. Such junctions are important throughout the body, and TJP2 is not specific to the liver. A mild form of liver disease associated with mutations in the TPJ 2 gene was previously called familial hypercholanaemia (which means high bile salts in blood). Only a small number of patients with PFIC caused by TJP2 mutation have been studied so far, so it is not yet understood of what manifestations, other than liver disease and its consequences that TJP2 deficiency patients may have.

This form of PFIC is caused by a mutation in the NR1H4 gene, which encodes the FXR (the Farnesoid X Receptor) protein. This protein 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 potentially very early in infancy. Only 4 patients have been reported so far, although it is expected more will likely be identified as this cause of PFIC is fairly newly described.

MYO5B is involved in maintaining proper functioning of cell membranes and helping to move proteins, such as BSEP, to where they are needed. MY05B has been related to intestinal disorder, cholestasis, or both. Some patients with cholestasis due to MYO5B deficiency have progressive liver disease, while others have it only intermittently.

Unidentified forms of PFIC

The mechanisms of the formation of bile are extremely complicated. As a result it is anticipated that many more genetic causes of PFIC will be identified. The identification of these mutations is very complicated and requires state of the art genetic investigations.

Although many PFIC patients have mutation in one of the genes mentioned above, there are still PFIC patients in whom mutations are not found in any of these genes. Genetic studies are underway to try to identify genetic factors contributing to PFIC in such patients.

Read more about:

Diagnosis and Treatment                The Itch              PFIC