• Potential conflict of interest: Nothing to report.

We appreciate the interest and the comments by Dr. Knisely about our work recently published in Hepatology,[1] in which we propose that a newly described mutation in the ABCB11 gene may predispose to benign recurrent intrahepatic cholestasis through a regulatory mechanism at the lobular level.

To adequately support this proposal, we examined the predicted pathogenicity of the c.221T>G mutation, which results in an amino acid change p.Ile74Arg in the first transmembrane domain. This mutation changes a weakly conserved amino acid and the physicochemical difference between Ile and Arg is moderate (Grantham score 97). In addition, this mutation could introduce a new splice acceptor site resulting in nonsense mediated messenger RNA (mRNA) decay.

We agree that immunohistochemically assessed expression of other canalicular transporter homologs of bile salt export pump (BSEP) such as the products of ABCB4 or ABCC2 could have been tested. However, cholestasis with normal GGT does not occur typically in patients carrying these mutations. The additional immunohistochemical staining of this patient's liver using anti-ABCB4 (MDR3) antibodies did not show any zonal distribution of this protein (Fig. 1). Moreover, all coding sequences, including the flanking intron sequences of the ABCB4 and ATP8B1 genes, were analyzed without evidence for pathogenic mutations in this patient.

Figure 1.

Canalicular immunohistochemical staining with anti-ABCB4 (MDR3) antibodies showing a homogeneous distribution of this protein also in zone 3 around the central vein (arrow).

Certainly we endorse the possibility of testing mutations of genes with products that specifically modulate the expression of wild-type BSEP,[2] but in this case gene-profiling experiments going beyond the design of this clinical case would be needed.

Furthermore, testing of affected family members would be helpful in determining whether cholestasis in this patient was due to the observed genetic change.

In conclusion, based on the genetic and new immunohistochemical results obtained in this patient, we suggest that the c.221T>G mutation, possibly in combination with other abnormalities, can contribute to the pathogenesis of BRIC 2. We share, however, Dr. Knisely's opinion that caution is needed when interpreting immunohistochemical studies and we underscore the need for further investigation of the association between this mutation and BRIC 2.

  • Sheida Moghadamrad, M.Sc.1

  • Matteo Montani, M.D.2

  • Andrea De Gottardi, M.D., Ph.D.1

  • 1Department of Clinical Research

  • Hepatology Study Group

  • University of Berne, Berne,

  • Switzerland

  • 2Department of Pathology

  • University of Berne, Berne,

  • Switzerland