The Natural Course of Bsep Deficiency: Results from the Global Napped- Consortium
(2018) AASLD Liver Meeting — Location: San Francisco, USA (9.November.2018)
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- Background: BSEP deficiency (BSEP-def), due to mutations in the ABCB11gene, is responsible for progressive familial intrahepatic cholestasis type 2. The ABCB11gene encodes the canalicular Bile Salt Export Pump (BSEP). BSEPdef patients typically present with pruritus and cholestasis in early life, that usually progresses to the need for liver transplantation (LTx). Patients may benefit from ursodeoxycholic acid (UDCA) or from surgical biliary diversion (SBD) techniques. We aim to better understand the natural course of BSEPdef and the efficacy of interventions. Methods: We present retrospective follow up data on patients with compound heterozygous or homozygous ABCB11mutations from 22 centers in Europe, North-America, Asia and Australia (the NAPPED-consortium,NAtural course and Prognosis of PFIC and Effect of biliary Diversion). In total 203 patients (53% males) wereincluded and categorized according to genotype: mild (at least one D482G or E297G mutation; n=68), moderate (at least one missense mutation, but not D482G or E297G; n=100) or severe (mutations leading to truncated or otherwise non-functional protein; n=35). Cox regression analysis was applied for the endpoints SBD and native liver survival (NLS) studying the association with gender, age at diagnosis, birth year, genotype category and SBD as a time-dependent factor for NLS. Continuous variables are expressed as median [range]. Results: Overall median age at first visit was 9 months [0-195] and at last follow up 5.5 years [0.1-31.4]. Use of UDCA at first visit was 47%. Overall SBD rates at five/ten years of age were 27/34%, mild category patients were more likely to have undergone SBD (HR mild vs severe = 5.4, 95%CI 1.7-17.6; p<0.01). Overall five/ten-year NLS was 63/46%. Age at diagnosis and genotype were associated with NLS, in contrast to sex and UDCA. NLS was significantly higher in SBD+ve than in SBD-ve patients (HR=0.44; 95%CI 0.23-0.88, p=0.007; Figure) after adjustment for age and genotype category. This effect was independent of mild or moderate BSEP mutationssignificantly associated with NLS (HR=0.76; 95%CI 0.07-7.88, p=0.81). Hepatocellular carcinoma (HCC) was diagnosed in 8% of all patients, at a median age 2.1 years [0.7 – 11.0], and was significantly associated with genotype: mild 3%; moderate 8%, severe 18% (p=0.04). The observed NLS at 18 years of age was 34%; for mild, moderate and severe patients 51%, 24% and 0%, respectively (p=0.004). Conclusion: The NAPPED consortium has generated the largest collection of data on patients with BSEP deficiency, allowing more detailed insights into the natural course of this disease. Only a third of BSEP patients reach adulthood with their native liver. The effect of surgical biliary diversion, native liver survival and the incidence of HCC were all associated with the severity category of the BSEP mutation.
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Van Wessel, D., Thompson, R. J., Sokal, E., & et al. (2018). The Natural Course of Bsep Deficiency: Results from the Global Napped- Consortium. AASLD Liver Meeting, San Francisco, USA. https://hdl.handle.net/2078.5/62393