APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
autosomal dominant
Genes: TJP2
BAAT

Familial hypercholanemia
FHCA

Itching
Pruritis
Fat malabsorption
Elevated bile acids
Failure to thrive
Vitamin K-dependent coagulopathy
Rickets

Hypercholanemia

Clinical Characteristics

General description (for patients):

This liver disease causes extensive itching, poor fat absorption, and can lead to rickets due to lack of calcium in bones.  The deficiency of normal bile acids in the intestines results in a deficiency of vitamin K which adversely affects clotting of the blood.  Vitamin D is another fat soluble vitamin which requires bile acids for proper absorption and blood levels.  Jaundice sometimes occurs but is not a reliable sign.  There is a great deal of variation in the severity of disease and some older children no longer require therapy which may be required to reduce symptoms in young children.  There is no information on this disease in adults.

Medical description: 

Bile acids are elevated in this disorder in the absence of the usual markers of hepatic cell damage although alkaline phosphatase activity is sometimes elevated.  Pruritis, failure to thrive, vitamin K-dependent coagulopathy, steatorrhea and rarely jaundice are part of the clinical picture.  Vitamin D malabsorption can lead to rickets.  Of the two gene mutations in the Lancaster Amish associated with  this phenotype, one, TJP2, encoding the tight junction protein2, is associated with observable changes in hepatic tight junctions that likely results in greater leakage of bile acids into plasma, while the other, BAAT, is a bile acid-conjugating enzyme, and results in the release of only unconjugated bile acids. Treatment with ursodiol can reduce symptoms although some older children no longer seem to need it.

Genetics:

FHCA is an interesting and unusual genetic disorder.  It can result from homozygous mutations in the TJP2 gene on chromosome 9 (9q12-q13, 143T>C) or from homozygosity of the BAAT gene (9q22-q32, 226A>G) both of which have been identified in the Lancaster Amish.  Curiously, several TJP2/TJP2 genotypes with FHCA also were heterozygous for the BAAT mutation, and one individual with the phenotype had neither mutation.  Further, three members of the pedigree who were homozygous for the TJP2 mutation did not have the phenotype, documenting incomplete penetrance of the phenotype and suggesting that other genes may be involved.

Treatment:

Ursodiol (ursodeoxycholic acid) can improve symptoms although it does not correct the genetic defect.

Prognosis:

Probably excellent although insufficient data from older individuals exists to determine long term prognosis.  Some youngsters become asymptomatic during the first decade while others in the same age range are still symptomatic.

Ancillary treatments and support:

Diet, bone density, and blood coagulation must be monitored.

Specialists and specialty centers:

Pediatrician, gastroenterologist, nutritionist.

References:

Carlton, V.E.H., Harris, B.Z., Puffenberger, E.G., Batta, A.K., Knisely, A.S., Robinson, D.L., Strauss, K.A., Shneider, B.L, Lim, W.A., Salen, G., Morton, D.H., and Bull, L.N.:  Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT.  Nature Genet. 34: 91-96, 2003.  PubMed ID: 12704386

Morton, D.H., Salen, G., Batta, A.K., Shefer, S., Tint, G.S., Belchis, D., Shneider, B., Puffenberger, E.G., Bull, L., and Knisely, A.S.:  Abnormal hepatic sinusoidal bile acid transport in an Amish kindred not linked to FUC1 and is improved by ursodiol.  Gastroenterology 119: 188-195, 2000.  PubMed ID: 10889168

Resources:

American Liver Institute

Associated Graphics