Bile salt export pump expression: Can immunohistochemistry in isolation mislead?


  • Potential conflict of interest: Nothing to report.

To the Editor:

Moghadamrad et al.[1] describe a woman with gallstones, intrahepatic cholestasis, and normal-range serum gamma-glutamyl transpeptidase activity; a single identifiable mutation in ABCB11 (encoding bile salt export pump, BSEP); and reduced expression by centrilobular hepatocytes of immunohistochemically demonstrable BSEP. They propose that the single-copy mutation found in ABCB11, c.221T>C/p.Ile74Arg, underlay cholestatic liver disease in their patient. I should like to believe them, but in my opinion their findings, as presented, do not adequately support their proposal.

Predicted pathogenicity of the c.221T>C mutation is not addressed and, regrettably, findings using appropriate immunohistochemical controls are not supplied. Immunohistochemically assessed expression of other canalicular transporters, homologs of BSEP such as the products of ABCB4 (multidrug resistance protein 3, MDR3) and ABCC2 (Dubin-Johnson protein/multidrug resistance-associated protein 2, MRP2), should have been described to permit the reader to judge if a generalized debility of adenosine triphosphate-binding cassette transporter expression, affecting centrilobular hepatocytes in particular, might have led nonspecifically to the abnormality of BSEP expression presented. The authors might also have discussed the possibility that mutation in genes with products that specifically modulate expression of wild-type BSEP, as reported for ATP8B1 through farnesoid X receptor,[2] contributed to the decreased BSEP expression that they report.

I caution investigators against reliance on immunohistochemical studies in which expression of an individual protein is assessed in isolation. I shall welcome information from Moghadamrad et al. on the predicted pathogenicity of the p.Ile74Arg substitution mutation in ABCB11, on results of immunostaining for MDR3 and MRP2 in their patient's liver-biopsy specimen, and on results of sequencing in their patient of genes with products that affect BSEP expression.

  • A.S. Knisely, M.D.

  • King's College Hospital

  • Institute of Liver Studies

  • London, UK