PFIC Progressive Familial Intrahepatic Cholestasis Flashcards
What is PFIC?
Progressive familial intrahepatic cholestasis (PFIC) refers to a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis. This usually leads to failure to thrive, hepatic failure, and the need for liver transplantation.
What are the main features of PFIC-1? Does this disease have another name? Which clinical feature, besides the classical ones, may be present in these patients?
PFIC-1 is caused by a variety of mutations in ATP8B1, a gene coding for a P-type ATPase protein, FIC-1, that is responsible for phospholipid translocation across membranes.[1] It was previously identified as clinical entities known as Byler’s disease and Greenland-Eskimo familial cholestasis. Patients with PFIC-1 may also have watery diarrhea, in addition to the clinical features below, due to FIC-1’s expression in the intestine. How ATP8B1 mutation leads to cholestasis is not yet well understood.
What are the main features of PFIC-2?
PFIC-2 is caused by a variety of mutations in ABCB11, the gene that codes for the bile salt export pump, or BSEP. Retention of bile salts within hepatocytes, which are the only cell type to express BSEP, causes hepatocellular damage and cholestasis.
What are the main features of PFIC-3?
PFIC-3 is caused by a variety of mutations in ABCB4, the gene encoding multidrug resistance protein 3 (MDR3),[2] which codes for a floppase responsible for phosphatidylcholine translocation. The defective phosphatidylcholine translocation leads to a lack of phosphatidylcholine in bile. Phosphatidylcholine normally chaperones bile acids, preventing damage to the biliary epithelium. The free or “unchaperoned” bile acids in bile of patients with MDR3 deficiency cause a cholangitis. Biochemically, this is of note, as PFIC-3 is associated with a markedly elevated GGT.
How is the inheritance pattern of PFIC?
The inheritance pattern of all three forms of PFIC defined to date is autosomal recessive.
What is expected from GGT, serum bile acid and cholesterol levels in PFIC?
Biochemical markers include a normal GGT for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3. Serum bile acid levels are grossly elevated. Serum cholesterol levels are typically not elevated, as is seen usually in cholestasis, as the pathology is due to a transporter as opposed to an anatomical problem with biliary cells.
What are the microscopic changes seen on PFIC?
Liver biopsies typically show evidence of cholestasis (including bile plugs and bile infarcts), duct hypoplasia, hepatocellular injury, and Zone 3 fibrosis. Giant cell change and other features of hepatocellular injury are more pronounced in PFIC-2 than in PFIC-1 or PFIC-3. End-stage disease in all forms of PFIC defined to date is characterized by bridging fibrosis with duct proliferation in peri-portal regions.[5]
What is the treatment for PFIC?
Initial treatment is supportive, with the use of agents to treat cholestasis and pruritus, including the following:
Ursodeoxycholic acid
Cholestyramine
Rifampin
Naloxone, in refractory cases
Patients should be supplemented with fat soluble vitamins, and occasionally medium-chain triglycerides in order to improve growth.
When liver synthetic dysfunction is significant, patients should be listed for transplantation. Family members should be tested for PFIC mutations, in order to determine risk of transmission.
