Progressive familial intrahepatic cholestasis (PFIC) is a rare hereditary disease in which the liver cells struggle to produce and secrete bile. Bile (the digestive fluid made by the liver) plays important roles to help remove toxins from the body and to break down fat in food. Therefore, in patients affected with PFIC, the lack of bile secretion also leads to unnecessary waste being kept in the blood stream, and the body not being able to absorb fats and fat-soluble vitamins (certain vitamins that are absorbed along with fats in the diet that can be stored in the body’s tissues) properly. In addition, there is a buildup of bile in liver cells (a form of cholestasis) which results in liver cell damage and can progress to more severe liver disease. The disease affects approximately one in every 50,000 to 100,000 births worldwide

What causes PFIC? ​

PFIC is inherited and is usually found in young infants and children.  In order to have the disease, a person must receive two of the genes for PFIC (autosomal recessive inheritance pattern), one from each parent.

The common genetic mutations associated with PFIC are as follows: ATP8B1, ABCB11, ABCB4, TJP2 and NR1H4 seen in patients with PFIC type 1, type 2, type 3, 4 and 5 respectively.

What are the symptoms of PFIC?

There are five known types of PFIC: PFIC type 1, PFIC type 2, PFIC type 3, PFIC type 4, and PFIC type 5. PFIC types 4 and 5 are exceedingly rare in the reported medical literature, however they are being recognized more. There are also other rare PFIC types that are currently being researched.  

With PFIC type 1, additional signs and symptoms include short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of vitamins A, D, E, and K. In PFIC type 1, liver failure will typically develop before adulthood.

With PFIC type 2, although the signs and symptoms related to liver disease are similar to patients with PFIC type 1, signs and symptoms will be more severe. Additionally, PFIC type 2 patients have an increased risk of developing liver cancer (hepatocellular carcinoma). In PFIC type 2, liver failure will typically occur in the first few years of life.

With PFIC type 3, the signs and symptoms related to liver disease do not usually appear until later in infancy or early childhood. Sometimes people get diagnosed with PFIC type 3 in adolescence or early adulthood, which is rare, however liver failure can occur in childhood or adulthood.

With PFIC type 4 and 5, there are some reports of increased risk of developing liver cancer as well as development of fat in your liver (fatty liver) following liver transplantation.  

Liver disease related symptoms and consequences include:

• pruritus (severe itching)
• jaundice (yellowing of skin and whites of eyes)
• fatigue
• enlarged liver or spleen
• cirrhosis
• liver cancer
• liver failure

Infants and children with PFIC may experience poor weight gain and slow growth since they are not able to absorb and digest fats and certain vitamins.

How is PFIC diagnosed?

Most people with PFIC show signs of disease in early infancy or childhood and sometimes in adolescence. Genetic testing will reveal if a person has PFIC or is a carrier of the disease. A carrier does not have the disease themselves but may pass the disease on to their children. Liver function tests can be done to check the state of the liver and the biliary system (gallbladder and bile ducts).

PFIC type 1 and PFIC type 2 are characterized by low to normal levels of the enzyme gamma-glutamyl-transferase (GGT), along with high levels of bilirubin (main bile pigment in humans) and bile acid levels, whereas PFIC type 3 is characterized by high GGT levels. Also, a test may be done to determine the bile salt concentration. In patients with PFIC, bile salt concentrations are 10-20x higher than normal. PFIC 4 and 5 have been found more recently and are continuing to be studied. 

There are currently five known genes responsible for PFIC (as described in section “What causes PFIC?”). However, some people can have PFIC without having a mutation in any of the known genes. Genetic testing continues to be an effective method of diagnosis and carrier status. Genetic testing can show whether the disease runs in the family and if any of the children are at risk for passing the disease on to their children.

How is PFIC treated?

Prescribed medication can be used to help bile flow in the bile ducts and liver as well as to relieve discomfort associated with symptoms of the disease; most notably the severe itching (pruritus). Ursodiol (also called ursodeoxycholic acid or UDCA) reduces elevated liver enzymes by easing bile flow through the liver. Rifampin (also called rifampicin) can be used to treat pruritus; however, the itching will only be partially improved, if at all.

Surgery can be used to reduce the flow of the bile acid into the liver. Partial external and internal biliary diversion (PEBD & PIBD), or ileal bypass (shortening the length of the small intestine), are all surgical options to reduce the circulation of bile acids into the liver and to help remove the bile acid from the blood stream

Vitamin supplements can be taken in order to replenish the vitamins A, D, E, and K that are not being properly absorbed by the body through the bile.

Other medical therapy for complications of liver cirrhosis may be required. Liver transplantation may be necessary if liver failure or liver cirrhosis occurs. In addition, liver transplantation may be considered if the itchiness and liver-related symptoms do not respond to conventional medical or surgical options.

Is there a cure for PFIC?

There is currently no cure for PFIC. On the other hand, liver transplantation is sometimes considered an effective option for PFIC. Other treatments, including surgery, are currently available and are used to manage symptoms of the disease.

What follow-up should occur with a new diagnosis of PFIC?

Since the gene carrying the disease is inherited (one from each parent), siblings of an affected individual have a 25 per cent chance of being affected. Therefore, when a new case is diagnosed, it is strongly recommended parents and all children be screened for the disease.

Blood levels of fat-soluble vitamins (A, D, E, and K) should be monitored regularly and vitamin supplementation may be needed if vitamin levels in the body are too low. Patients could speak with a registered dietitian and/or their doctor about fat-soluble vitamin deficiency.