APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
Genes: ATP8B1

Byler disease
Fatal intrahepatic cholestasis type 1
PFIC1

Jaundice
Liver cirrhosis
Liver scarring
Bile disorder
Malnutrition
Hepatomegaly
Splenomegaly
Steatorrhea
Growth retardation
Elevated level of liver enzymes
Canalicular cholestasis
Bile duct loss
Abnormal intraductal epithelium

Cholestasis, Familial Intrahepatic

Clinical Characteristics

General description (for patients):

This is a progressive hereditary form of liver scarring and failure.  It is first noted in infants with loose, foul-smelling stools, evidence of malnutrition, yellow jaundice, enlarged liver and spleen.  The result is delayed growth, and in the absence of a liver transplant, death in the first decade.

Medical description: 

PFIC is one of a heterogeneous group of progressive liver failure disorders as a result of a defect in the transport of bile acids.  Signs and symptoms begin in the neonatal period with fatty, odiferous stools, and hyperbilirubinemia.  Pruritis may be a prominent symptom.   Hepatosplenomegaly, malnutrition, and growth retardation become evident early, with end stage cirrhosis and fibrosis developing in the first decade.  Liver enzymes are elevated and biopsies show canalicular cholestasis, bile duct loss, and abnormal intraductal epithelium.

Genetics:  

This form of intrahepatic cholestasis is caused by a mutation in the ATP8B1 gene on chromosome 18 (18q21) which encodes a bile salt ATP-binding cassette transporter.  It is but one type of autosomal recessive PFIC in which the transport of bile acids is defective.  Like the others, it begins prenatally, and progresses to hepatic fibrosis, cirrhosis, and end stage liver disease before adulthood.  Multiple mutations in ATP8B1 have been found and a specific one, 923G>T, is responsible for the disease in the Lancaster Amish of Pennsylvania.  At least two other mutations causing cholestatic disorders, benign recurrent intrahepatic cholestasis (BRIC), and intrahepatic cholestasis of pregnancy (ICP) are allelic.

Treatment:  

The only effective treatment in PFIC1 is orthotopic liver transplantation.

Prognosis:  

This disease is fatal without a liver transplant.

Ancillary treatments and support: 

Antipruritic medications can have a role in severe cases.

Specialists and specialty centers: 

Gastroenterologist, pediatrician, nutritionist

References:

Bull, L.N., van Eijk, M.J.T., Pawlikowska, L, DeYoung, J.A., Juijn, J.A., Liao, M., Klompp, L.W.J., Lonri, N., Berger, R., Scharschmidt, B.F., Knisely, A.S., Houwen, R.H.J., and Freimer, N.B.:  A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.  Nature Genet. 18: 219-224, 1998.  PubMed ID: 9500542

Clayton, R.J., Iber, F.L., Ruebner, B.H., and McKusick, V.A.:  Byler disease: fatal familial intrahepatic cholestasis in an Amish kindred.  Am. J. Dis. Child. 117: 112-124, 1969.  PubMed ID: 5762004

Alonso, E.M., Snover, D.C., Montag, A., Freese, D.K., and Whitington, P.F.:  Histologic pathology of the liver in progressive familial intrahepatic cholestasis.  J. Pediat. Gastroent. Nutr. 18: 128-133, 1994.  PubMed ID: 8014759

Resources:

Cholestatic Liver Disease Consortium
American Liver Foundation

Associated Graphics