Rare and severe type of cholestasis liver disease,
beginning in infancy and progressing to cirrhosis before adolescence.
Cholestasis Progressive Familial Intrahepatic type I (PFIC I; Byler Disease; Fatal
Intrahepatic Cholestasis): with low level of gamma-glutamyl transferase (GGT); gene
ATP8B1 (previously termed FIC 1) mapped on 18q21.
Cholestasis Progressive Familial Intrahepatic type II (PFIC II): with a low level of GGT; gene ABCB11
(previously termed BSEP) mapped on 2q24.
Cholestasis Progressive Familial Intrahepatic type III (PFIC III; MDR 3 Deficiency; Progressive Intrahepatic
Cholestasis with Elevated Serum Gamma-Glutamyltransferase Syndrome): with a high level of
GGT; gene MDR3 mapped on 7q21.1.
Cholestasis Progressive Familial Intrahepatic type IV
First described by Clayton, in 1965, in an Amish
descendant of Jacob Byler.
The exact frequency is unknown in the United States and internationally. Fewer than 200
patients have been reported for the low-GGT PFIC, whereas less than 20 are known in the
high-GGT PFIC type. It is a lethal medical condition in childhood if not treated. Males
and females are affected equally.
Autosomal recessive (majority of patients),
also autosomal dominant with variable penetrance, or sporadic. Type II is
found in the Middle East, Greenland, and Sweden.
Type I seems to be caused by a defect in bile salt
synthesis. Type II seems to be caused by defective bile salt secretion. Type
III is caused by a mutation in MDR3 protein, which mediates the
translocation of phosphatidylcholine across the canalicular membrane of the
Symptoms of cholestasis (pruritus and jaundice) appear
in the first few months of life. Serum GGT activity is low to normal in type
I and type II, and elevated in type III. Cholesterol serum is normal.
Cholangiography shows normal morphology of intraand extrahepatic ducts.
Liver biopsy in type I and type II is characterized by the absence of true
proliferation of ducts within the liver and only periportal biliary metaplasia of
hepatocytes. In type III, liver histology is characterized by ductular
proliferation and inflammatory infiltrate.
Initially, episodes of severe cholestasis
followed by intervals of good health. Pruritus is typically severe (more than the
degree of bilirubinemia). Evolution is characterized by growth retardation,
hepatomegaly, and then cirrhosis, hepatic failure, and death early during the
childhood if not treated. Hepatocellular carcinoma may be present at age 2 years.
Consequences of cholestasis (neurological anomalies caused by vitamin E
deficiency, skin excoriations because of pruritus, rickets because of
vitamin D deficiency, epistaxis as a result of coagulopathy or
thrombocythemia). Pancreatic anomalies in type II may be present. In type
III, symptoms appear later with a slower evolution. Jaundice is less visible
and pruritus less intense.
Obtain a complete medical history of cholestatic
episodes and their frequency and clinical consequences: if of prolonged duration, inquire about
parenteral fat-soluble vitamins supplementation (deficiency of vitamin D:
rickets, osteomalacia; vitamin K: coagulation disorders; ...