Progressive familial intrahepatic cholestasis

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.

Pathogenesis and epidemiology

PFIC-1 is characterized by a mutation in FIC-1, a P-type ATPase gene coding for a protein responsible for phospholipid translocation ^*. 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.

PFIC-2 is caused by a variety of mutations in the gene that codes for the bile salt export pump, or BSEP; over fifteen such mutations have been identified. Epidemiologically, PFIC-2 is most commonly seen in Middle Eastern and northern African countries.

PFIC-3 is characterized by mutations in the MDR3 gene ^*, which codes for a flipase responsible for phosphatidylcholine translocation. The defective phosphatidylcholine translocation leads to damage to the biliary epithelium, leading to a cholangitis. Biochemically, this is of note, as PFIC-3 is associated with a markedly elevated GGT. PFIC-3 has a significantly higher incidence in South America, particularly in Chile.

The inheritance pattern is autosomal recessive.

Clinical presentation and natural history

The onset of the disease is usually before age 2, but patients have been diagnosed with PFIC even into adolescence. Of the three entities, PFIC-3 usually presents earliest. Patients usually present in early childhood with cholestasis, jaundice, and failure to thrive. Intense pruritus is characteristic; in patients who present in adolescence, it has been linked with suicide. Patients may have fat malabsoprtion, leading to fat soluble vitamin deficiency, and complications, including osteopenia. ^*

Biochemical markers include a normal GGT for PFIC-1 and -2, with an 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.

The disease is typically progressive, leading to fulminant liver failure and death in childhood, in the absence of liver transplantation.

Pathology

Liver biopsies typically show evidence of cholestasis (including bile plugs and bile infarcts), duct paucity, peri-portal hepatocellular injury, and Zone 1 fibrosis. End-stage pathology shows bridging fibrosis with duct proliferation in peri-portal regions ^*.

Treatment

Initial treatment is supportive, with the use of agents to treat cholestasis and pruritus, including the following:

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.

Associations

Consanguinity is believed to be a major risk factor
Similar transport protein mutations are believed to pose a higher risk for intrahepatic cholestasis of pregnancy.

References

Support groups - pediatric

Liver Families

Gastroenterology | Pediatrics | Genetic disorders | Hepatology

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