Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis

Background & Aims: Progressive familiar intrahepatic cholestasis (PFIC), an inherited liver disease of childhood, is characterized by cholestasis and either normal or increased serum gamma-glutamyltransferase activity. Patien ts with normal gamma-glutamyltransferase activity have mutations of the FIC 1 locus on chromosome 18q21 or mutations of the BSEP gene on chromosome 2q2 4, Also, patients with bile acid synthesis defects have low gamma-glutamylt ransferase activity. We investigated expression of the bile salt export pum p (BSEP) in liver samples from patients with a PFIC phenotype and correlate d this with BSEP gene mutations, Methods: BSEP and multidrug resistance pro tein 2 (MRP2) expressions were studied by immunohistochemistry in liver spe cimens of 28 patients and BSEP gene mutation analysis in 19 patients. Bile salt kinetics were studied in 1 patient. Results: Sixteen of 28 liver sampl es showed no canalicular BSEP staining. Staining for MRP2 showed a normal c analicular pattern in all but 1 of these samples. Ten of 19 patients showed BSEP gene mutations; BSEP protein expression was lacking in all 10 patient s, No mutations were found in 9 of 19 patients, and in all except 1, BSEP p rotein expression was normal. Bile salt concentration in bile of BSEP-negat ive/MRP2-positive PFIC patients was 0.2 +/- 0.2 mmol/L (n = 9; <1% of norma l) and in BSEP-positive PFIC patients 18.1 +/- 9.9 mmol/L (n = 3; 40% of no rmal). The kinetic study confirmed the dramatic decrease of bile salt secre tion in BSEP-negative patients. Conclusions: The findings show a close corr elation between BSEP gene mutations and canalicular BSEP expression. Biliar y secretion of bile salts is greatly reduced in BSEP-negative patients.