Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a chronic cholestasis syndrome that begins in infancy and usually progresses to cirrhosis within the first decade of life. The average age at onset is 3 months, although some patients do not develop apparent cholestasis until later, even as late as adolescence. PFIC can progress rapidly and cause cirrhosis during infancy, or it may progress relatively slowly with minimal scarring well into adolescence. Few patients have survived into the third decade of life without treatment.

The condition clinically characterized by hepatocellular cholestasis, low serum levels of gamma-glutamyl transferase (GGT) activity, and autosomal recessive inheritance is termed low-GGT PFIC. Initially described in Amish descendants of Jacob Byler, the condition was originally named Byler disease. Subsequently, numerous phenotypically similar non-Amish patients were reported, and the term Byler syndrome was used to describe these patients’ condition. These terms now have been superseded by the term PFIC.

At present, specific gene defects have been identified for 2 subtypes of low-GGT PFIC: PFIC-1 (the former Byler disease) and PFIC-2. Despite their genetic distinctiveness, PFIC-1 and PFIC-2 have few clinical differences, and both are caused by the absence of a gene product function for canalicular export and bile formation.

Patients with familial intrahepatic cholestasis but with high serum GGT have a condition termed high-GGT PFIC. These patients manifest severe progressive intrahepatic cholestasis in the first year and progress toward hepatic failure in the first few years of life. Liver biopsy results reveal expanded portal areas with proliferation of interlobular bile ducts plugged with bile, suggesting an obstructive disorder rather than a primary defect in bile formation.

Pathophysiology
Several lines of evidence point to a defect in canalicular bile acid transport with primary retention of hydrophobic bile salts as the mechanism of disease in patients with low-GGT PFIC. This conclusion is supported by the differences in the quantitative and qualitative distribution of bile acids in serum and bile. Total serum bile acid concentrations are markedly elevated (ie, usually >200 mmol/L compared to normal concentrations of <10 mmol/L); the ratio of chenodeoxycholic acid to cholic acid conjugates is elevated, usually more than 10:1. Total biliary bile acid concentrations are low (ie, 0.1-0.3 mmol/L, compared to normal concentrations of >20 mmol/L) and with a predominance of cholic acid conjugates. These findings suggest a defect in biliary excretion, particularly of chenodeoxycholic acid conjugates.

The gene for PFIC-1 has been mapped to a 19 cM region at band 18q21-22 by the detection of a preserved haplotype in affected members of the Byler pedigree. In the process of closely examining the region, a gene named FIC-1 that contains an ATP-binding cassette (ABC) was identified and is being investigated as a transporter of phospholipids and/or bile salts.

Patients from 6 consanguineous families of Middle Eastern origin were found to have a defect in the gene FIC-2, located at band 2q24; this defect has been designated PFIC-2. The FIC-2 gene is analogous to the rat sister gene of p-glycoprotein (S-PGP), an ABC bile salt transporter also called the bile salt export pump (BSEP). In rats, S-PGP is important in bile salt transport, and this discovery provides evidence that FIC-2 is an important human bile salt export pump.

In a recent study using immunohistochemistry, liver tissue from cholestatic patients with defects in FIC-2 did not express BSEP in the canalicular domain, while tissue for other familial cholestasis patients did. This suggests that in most patients with PFIC-2, the gene defect is sufficiently severe to produce no product or a protein that cannot be inserted into the canalicular membrane. This technique may provide a means of diagnosing PFIC-2 in the clinical setting.

Several clinical differences have been reported between patients with PFIC-2 and patients with PFIC-1, though the distinction remains in question. Clinically, patients with PFIC-2 seem to lack the relapsing course seen in the early stages of PFIC-1 and, instead, have a more rapidly progressive course to fibrosis. Light microscopy and transmission electron microscopy demonstrate that liver tissue from patients with PFIC-1 has coarse granular bile and bland canalicular cholestasis, whereas patients with PFIC-2 have amorphous or finely filamentous bile and neonatal hepatitis.

Patients with PFIC-1 are more likely to have associated watery diarrhea, some of which is severe. This secretory diarrhea may persist after liver transplantation and may reflect an important role for FIC-1 in the intestine, where it is expressed in quantity. Work continues to resolve issues related to phenotype and response to therapy, and conclusions must await the identification of the gene defects involved in a large number of patients.

Further genetic heterogeneity may exist in PFIC because several families with clinical and biochemical features consistent with PFIC do not have linkage to either the 18q region (those with PFIC-1) or the 2q region (those with PFIC-2). A defect in the sinusoidal uptake of bile salts recently was described in 4 related Amish children. The proband expressed a PFIC phenotype, while 3 siblings expressed only elevated serum bile salt concentrations. Microsatellite markers for the 18q region in these 4 children were inconsistent with linkage to FIC-1. All responded to treatment with ursodeoxycholic acid.

The pathophysiology for high-GGT PFIC is very different. Mutations in MDR-3 were identified as responsible after analysis of bile showed very low concentrations of phospholipid and after the phenotype of the analogous Mdr-2 knockout mouse had been described.