Impact of genotype on childhood bile salt export pump deficiency in Indian Progressive Familial Intrahepatic Cholestasis registry
Seema Alam, Bikrant Bihari Lal, Karunesh Kumar, Anupam Sibal, Vaibhav Shah, Somashekara Hosaagrahara Ramakrishna, Ira Shah, Zahabiya Nalwalla, Pandey Snehavardhan, Ashish Bavdekar, Nishant Wadhwa, Arjun Maria, Subhash Gupta, Aabha Nagral, Nirmala Dheivamani, Aniket Deshmukh, Lalit Verma, Anuradha Rai, Aathira Ravindranath, Sanjeev Kumar Verma, Aashay Shah, A. Ashritha, Arya Suchismita, Yogesh Waikar, Parijat Ram Tripathi, Piyush Upadhyay, John Matthai, Smita Malhotra, Vipul Gautam, Vikram Kumar, Dulasi Durga, Nowneet Kumar Bhat, Maya Peethambaran, K. P. Srikanth, Viswanathan M. Sivaramakrishnan, Vikrant Sood, Rajeev KhannaAbstract
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).