Genotype Correlates with the Natural History of Severe Bile Salt Export Pump Deficiency

Short Background:

The ABCB11gene provides the code to build the bile salt export pump (BSEP) protein. In this paper, “genotype” refers to the type of mutations of the ABCB11gene that can cause severe BSEP deficiency. Liver disease caused by BSEP deficiency is known as PFIC 2. A “missense mutation” is a mutation of just one base pair of a gene. This can be thought of as just one wrong letter in the code, but the effects of such a missense mutation can still be very severe. It is possible that the protein is not built correctly, does not function correctly, or is not built at all.


This article describes the largest study to date of patients with severe BSEP deficiency. The authors categorized a total of 264 patients into three groups according to their type of mutation. The first group, BSEP 1, consisted of 72 patients with at least one D482G or p.E297G mutation. If the ABCB11gene has either of these mutations it can still produce some BSEP protein but not enough. The second group, BSEP 2, had 136 patients with at least one missense mutation (but not D482G or p.E297G). The patients in this group differed a lot with respect to the type of missense mutation. The third group, BSEP 3, had mutations that were known to lead to absence of the BSEP protein or to a non-functioning BSEP protein. The authors suspected that the severity of the effect of the mutation was the least in the BSEP1 group, followed by the BSEP 2 group, and BSEP 3 group.

            The goal of the study was to look whether the groups indeed differed with respect to outcomes such as the success of surgical biliary diversions (SBD), how long a patient lived with the native liver after SBD, and liver carcinoma (cancer of the liver).

            All three groups of patients had symptoms of PFIC 2 within their first year of life, and had very similar lab data initially. However, the course of disease differed between the groups. The first group, BSEP 1, had the least severe outcomes. For instance, relief of pruritis (itch) after surgical biliary diversion (SBD) was better, the number of years living with the native liver after SBD was longer, and the risk of liver cancer was the least compared to the other two groups. The second group also seemed to benefit from SBD: relief from pruritis and numbers of years with the native liver after SBD were better than the third group. The third group, BSEP 3, had generally the worst outcomes. In this group the authors did not see any improvement in itch relief after SBD. Also, the risk of liver cancer was substantially higher (about 34%) in this group.

            The authors conclude the type of mutation of the ABCB11gene is related to the severity of the disease. The results of this large study are consistent with previous smaller studies. The authors also note that the BSEP 2 group lumped together patients with different missense mutations, and that it would be good to conduct more research to get a more detailed picture whether these differences play a role in the severity of PFIC 2.


PFIC 2, BSEP deficiency, type of mutation


Van Wessel et al. Genotype Correlates with the Natural History of Severe Bile Salt Export Pump Deficiency. Journal of Hepatology, 2020

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