PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 1 (PFIC1)
ATP8B1 Sequencing
MITOCHONDRIAL ANALYSIS
Also known as: Benign Recurrent Intrahepatic Cholestasis 1 (BRIC1); Byler Disease

Description:

The ATP8B1 gene product resides in the hepatocyte canalicular membrane (as well as other epithelial membranes, e.g., enterocytes) whose function is not fully understood, but is clearly involved in bile acid transport across the canalicular membrane. Patients with impaired function of ATP8B1 have markedly low levels of bile acids in bile, leading to hepatocytic retention of bile acids, and subsequent progressive resultant hepatocellular damage. Impaired gut function of ATP8B1 is associated with severe nutritional consequences, including diarrhea and deficiencies of fat-soluble vitamins. Progressive familial intrahepatic cholestasis1 (PFIC1, Byler Disease, OMIM #211600) is a chronic autosomal recessive disorder due to impaired function, or mutations of the ATP8B1 gene, causing hepatomegaly, cholestasis, pruritus, hepatic fibrosis, cirrhosis, and various degrees of impairments of gut function (diarrhea). Heterozygous individuals may suffer from intermittent bouts of cholestasis, pruritus, and diarrhea, a condition known as benign recurrent intrahepatic cholestasis (BRIC). A principal confounder to PFIC1 is PFIC2, deficiency of the bile salt export pump (test # 3310) since both disorders lead to hepatocellular bile acid retention, lab tests notable for high serum bile acids with low/normal levels of gamma-glutamyltranspeptidase (low GGT cholestasis), and mutations of either gene can lead to clinical features of BRIC. PFIC1 patients may have features of extrahepatic disease--diarrhea, failure to thrive, pancreatitis, deafness, which is not seen in PFIC2 patients. Histological findings note hepatocellular cholestasis, giant cell transformation, and granular “Byler bile” within canaliculi found on electron microscopy. Many patients with mutations in ATP8B1 require close attention to nutrition and liver function, since they may ultimately require consideration for supplementation, biliary diversion, or liver transplantation.

Reasons for Referral:

Confirmation of a clinical diagnosis
Carrier testing

Testing Methodology:

The exons and flanking intron regions of ATP8B1 gene are PCR amplified and sequenced.

Specimen Requirements:

Blood: EDTA (purple-top) tubes: Adult: 14 cc; Child: 6 cc; Infant: 2-3 cc

Turnaround Time:

5 weeks

CPT Codes and Prices:

Index: 83891, 83898x27, 83904x54, 83912, 83894x2
Known Familial Mutation: 83904x4, 83898x2, 83912, 83891, 83894x2

Shipping Information

Forms:

>> Gene Sequencing Requisition or Mitochondrial Requisition - Mitochondrial Diagnostic Checklist is included

References:

1. Klomp L et al (2004). Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 40: 27-38.
2. Bull LN, van Eijk MJT, Pawlikowska L, DeYoung JA, Juijn JA, Liao M, Klomp LWJ, Lomri N, Berger R, Scharschmidt BF, Knisely AS, Houwen RHJ, Freimer NB (1998). A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 18: 219-224.
3. Oude Elferink RP, Paulusma CC, Groen AK (2006). Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology 130: 908-925.

Test Codes:

Index: 3305
Known Familial Mutation: 3306