PFIC is a rare genetic disorder that is estimated to affect between one in every 50,000 to 100,000 children born worldwide and causes progressive, life-threatening liver disease. There are currently no approved drug therapies for PFIC. Based on those estimated incidences, we project there are 3,200 children with PFIC in the United States and 5,000 in the European Union.
The most prominent and problematic ongoing manifestation of PFIC is pruritus, which leads to a severely diminished quality of life.
In many cases, PFIC leads to cirrhosis and liver failure within the first 10 years of life, and nearly all children with PFIC will require treatment before age 30. There are no medicines currently approved for PFIC, only surgical options – including a procedure known as Partial External Biliary Diversion (PEBD) or liver transplantation. These options carry substantial risk of post-surgical complications, as well as psychological and social issues.
Three alternative gene defects have been identified that correlate to three separate PFIC subtypes known as types 1, 2 and 3.
• PFIC, type 1, which is sometimes referred to as “Byler disease,” is caused by impaired bile secretion due to mutations in the ATP8B1 gene, which codes for a protein that helps to maintain an appropriate balance of fats known as phospholipids in cell membranes in the bile ducts. An imbalance in these phospholipids is associated with cholestasis and elevated bile acids in the liver. Children affected by PFIC, type 1 usually develop cholestasis in the first months of life and, in the absence of surgical treatment, progress to cirrhosis and end-stage liver disease before the end of the first decade of life.
• PFIC, type 2, which is sometimes referred to as “Byler syndrome,” is caused by impaired bile salt secretion due to mutations in the ABCB11 gene, which codes for a protein, known as the bile salt export pump, that moves bile acids out of the liver. Children with PFIC, type 2 often develop liver failure within the first few years of life and are at increased risk of developing a type of liver cancer known as hepatocellular carcinoma.
• PFIC, type 3, which typically presents in the first years of childhood with progressive cholestasis, is caused by mutations in the ABCB4 gene, which codes for a transporter that moves phospholipids across cell membranes.
Recently, TJP2 gene, NR1H4 gene or Myo5b gene mutations have been proposed to be causes of PFIC. In addition, some patients with PFIC do not have a mutation in any of the ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 or Myo5b genes. In these cases, the cause of the condition is unknown.