Impact of genotype on childhood bile salt export pump deficiency in Indian Progressive Familial Intrahepatic Cholestasis registry

BACKGROUND: A mutation in the ABCB11 gene causes the bile salt export pump (BSEP) deficiency. We aimed to study the genotype-phenotype correlation and the native liver survival (NLS) of BSEP deficiency among Indian children. METHODS: The data were retrieved from the Indian Progressive Familial intrahepatic Cholestasis (PFIC) registry. RESULTS: Among those enrolled in the registry, BSEP deficiency was the commonest (138/447, 30.9%) disorder. Among the 116 biallelic mutations, BSEP India1 (biallelic missense mutations) were present in 55 (47.4%) cases, whereas BSEP India2 (protein truncating mutation in at least one allele) in 17 (14.6%) cases, and BSEP India3 (biallelic protein truncating mutations) was seen in 44 (39.7%) cases, respectively. Of the 110 cases who presented with jaundice, in 36 (32.7%) cases jaundice resolved on urosdeoxycholic acid. Of the total, 91 with pruritus, grade 3 and 4 of pruritus was present in 54 (59.3%) cases, 43 (47.25%) cases did not resolve on medical management. On analysis of variance, median values of serum albumin (F-statistics 4.75, p = 0.011) were significantly lower in BSEP India3 versus BSEP India1 within the group. Risk predictive factors at baseline for death and LT were BSEP India3 (adjusted odds ratio [OR] 6.1, 95% confidence interval [CI] 1.9-19.3, p = 0.002) and grade 3 and 4 of pruritus (adjusted OR 5.9, 95% CI 2-17.1, p < 0.001). Kaplan-Meier survival analysis showed that non-resolution of jaundice, higher grade of pruritus and BSEP India3 was associated with significantly shorter duration of NLS. There were 49 likely novel mutations in various combinations and 2 PTMs (c.2115C>A [p.Tyr705Ter] and c.3659_3660del [p.Ser1220Ter]) as part of BSEP India3 genotype, were shown to be associated with death and liver transplantation (LT) in this Indian cohort. CONCLUSION: BSEP deficiency/ABCB11 mutation was the commonest PFIC seen in the registry. Risk predictive factors at baseline for death and LT were BSEP India3 and grades 3 and 4 of pruritus. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05704517 (retrospective study).