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.

Summary:

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.

Keywords:

PFIC 2, BSEP deficiency, type of mutation

Citation:

Van Wessel et al. Genotype Correlates with the Natural History of Severe Bile Salt Export Pump Deficiency. Journal of Hepatology, https://doi.org/10.1016/j.jhep.2020.02.007. 2020

Summary:

The goal of this study is to assess the outcomes of partial external biliary diversion (PEBD), ileal exclusion (IE), and liver transplant (LTX). The authors analyzed data from 102 patients who underwent one or more of these three procedures. In this cohort 42 patients had FIC1 deficiency (PFIC1) and 60 had Bile Salt Pump Export Protein (BSEP) deficiencies (PFIC2). The BSEP group was further split into two groups because other research has indicated that some mutations may result in more severe illness. More specifically, while some mutations may totally eliminate BSEP function, it is possible that two common mutations (D482G and E297G) may result in partial function of the BSEP protein, and less severe disease. This latter group was called “BSEP-common”, and the potentially more severe group “BSEP-other”.

            The authors of this paper looked at a number of different outcomes such as the effect on pruritis (itch), growth, progression to liver cirrhosis after PEBD, and liver function after transplant.

The effect of PEBD on pruritis showed sustained improvement in 57% of the FIC1 group, and 76% in the BSEP group with either the D482G or E297G mutation. However, in the BSEP group with other mutations the improvement percentage was only 33%.

More patients in the BSEP-other group progressed to cirrhosis compared to FIC1 patients and were listed for or underwent liver transplant. Outcomes after transplant showed that BSEP patients in general fared better than FIC1 patients. This is most likely due to the fact that the FIC1 protein not only plays an important role in the liver, but also in for instance the small and large intestine. Specifically, fatty liver (steatosis) was found in 19 out of 21 FIC1 patients with available data, but only in 2 out of 31 BSEP patients. In addition, diarrhea was reported in 81% of the FIC1 group vs. 7% in the BSEP group, and 8 FIC1 patients had pancreas problems vs. none in the BSEP group.

The general line of results indicated that the BSEP-common group (mutations in D482G and E297G) had more positive outcomes. This is consistent with the idea that these specific mutations still allow for partial functioning of the BSEP protein whereas other mutations may completely eliminate BSEP functioning. This study also supported the idea that FIC1 deficiency is a multi-system disease. This result indicates that liver transplant alone might not alleviate all symptoms in FIC1 patients, and should possibly be combined with PEBD to avoid fatty liver (steatosis).

Keywords:

FIC1 deficiency, BSEP deficiency, D482G, E297G, PEBD, transplant

Citation:

Bull et al. Outcomes of Surgical Management of Familial Intrahepatic Cholestasis Type 1 and 2. Hepatology Communications, 2(5), 515-528. 2018

Summary:

This article focusses on the potential reoccurrence of symptoms after liver transplant in PFIC 2 patients. PFIC 2 is caused by mutations in the bile salt export pump (BSEP), leading BSEP to function poorly or not at all (BSEP deficiency). This in turns leads to build up of bile salts in the liver (cholestasis). Depending on severity, liver transplant is often the only working treatment option. However, some PFIC 2 patients seem to develop BSEP deficiency again after liver transplant.

The researchers investigated the potential causes in 9 patients who had undergone liver transplantation previously, and showed that some of these patients had developed antibodies that inhibit BSEP between 3 and 108 months post-transplant. This is called antibody induced BSEP deficiency, AIBD, and it seems to occur in severely affected patients who have complete BSEP deficiency before transplant.

Keywords:

PFIC 2 Post-transplant, BSEP deficiency, AIBD

Citation:

Stindt et al. Bile Salt Export Pump-Reactive Antibodies Form a Polyclonal, Multi-Inhibitory Response in Antibody Induced Bile Salt Export Pump Deficiency. Journal: Hepatology, Vol. 63, No. 2 Year: 2016.