Vagaries of impaired transporter function in PFIC 2 and 3


  • Potential conflict of interest: Nothing to report.

Vagaries of Impaired Transporter Function in PFIC 2 and 3

The study by Keitel et al.1 on the expression and localization of hepatobiliary transport proteins in PFIC-2&3 intriguingly demonstrated the upregulation of MRP4, rather than MRP3. There are, however, two concerns about the control group: (1) adult livers may not be entirely suitable controls for the livers of juvenile patients with PFIC, because expression of transporters might vary with age; and (2) the ursodeoxycholic acid administered to the patients, but not the controls, could have affected the expression of the hepatic transporters, as it does in normal mice2 and in rats with cholic acid-induced cholestasis.3

A striking finding, that was not discussed, was the markedly higher levels of plasma bilirubins in two of the patients with PFIC-2 and two of the patients with PFIC-3, and the lack of correlation of these levels with concentrations of plasma bile salt and γ-glutamyltranspeptidase activity (γ-GT). Indeed, only the two patients with PFIC-3 and plasma bilirubin levels above 10 mg/dL lacked the marked γ-GT elevations, that were previously thought to be the hallmark of PFIC-3.4 Because pure unconjugated hyperbilirubinemia rarely causes such high levels of plasma bilirubin,5 it seems likely that the four jaundiced patients had conjugated hyperbilirubinemia, related to additional or different abnormalities in the expression of transporters of bilirubin conjugates.

MRP1 mRNA expression was increased in the patients with PFIC-3 but not PFIC-2; protein expression was not reported. MRP1 exports unconjugated bilirubin from cells,6 but it is unknown if it also transports bilirubin conjugates. MRP3 expression was spuriously high in one very jaundiced PFIC patient (C10), but not, apparently, in the other three. This result contrasts with the uniformly marked upregulation of MRP3/Mrp3 in the liver of Gunn rats with unconjugated hyperbilirubinemia due to Ugt1a1 deficiency,7, 8 in humans with conjugated hyperbilirubinemia due to MRP2 deficiency (Dubin-Johnson Syndrome)9 or primary biliary cirrhosis,10 and in rats8 and humans11 with obstructive cholestasis. Among patients with PFIC-2 or -3, mean expression of MRP4 was strikingly elevated, and expression of OATP1B1 and OATP1B3 was moderately depressed; each alteration might engender retention of conjugated bilirubin.12 Mean expression of MRP2, a canalicular exporter of conjugated bilirubin,9 was depressed by half in both groups of subjects, as reported in obstructive cholestasis in humans and rats.11, 13 Even in the complete absence of MRP2/Mrp2, however, there is some residual bilirubin excretion (e.g., in TR- rats14 and, except when complicated by fever or estrogen treatment, the serum bilirubin levels in Dubin-Johnson syndrome are rarely as high as in some of these PFIC patients.15 Hence, although downregulation of MRP2 may contribute to the hyperbilirubinemia in the PFIC patients, defects in other transporter(s) must be involved also.

The data presented do not point to a direct role for any of the studied transporters in the severe hyperbilirubinemia in the four PFIC patients. Correlation of transporter protein expression with plasma bilirubin levels among individual PFIC patients might reveal which transporter(s) could account for the uniquely high bilirubin levels in these four patients.

J. Donald Ostrow*, Claudio Tiribelli†, * GI/Hepatology Division, University of Washington, Seattle, WA, USA, † Liver Study Center (CSF), AREA Science Park and University of Trieste, Trieste, Italy.