Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export
pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity
of the disease, the associations between genotype and natural history, or outcomes
following surgical biliary diversion (SBD), remain elusive. We aimed to determine
these associations by assembling the largest genetically defined cohort of patients
with severe BSEP deficiency to date. Methods: This multicentre, retrospective cohort
study included 264 patients with homozygous or compound heterozygous pathological
ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1,
BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each
category. Results: Genotype severity was strongly associated with native liver survival
(NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p<0.001). At 15
years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1,
7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased
NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile
acid concentration below 102 mu mol/L or a decrease of at least 75%, each shortly
after SBD, reliably predicted NLS of >= 15 years following SBD (each p<0.001). Conclusions:
The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of
developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum
bile acid parameters shortly after SBD can predict long-term NLS. Lay summary: This
study presents data from the largest genetically defined cohort of patients with severe
bile salt export pump deficiency to date. The genotype of patients with severe bile
salt export pump deficiency is associated with clinical outcomes and the success of
therapeutic interventions. Therefore, genotypic data should be used to guide personalized
clinical care throughout childhood and adulthood in patients with this disease. (C)
2020 European Association for the Study of the Liver. Published by Elsevier B.V. All
rights reserved.
