ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

Abstract

Background & Aims: ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient neonatal cholestasis (TNC). Methods: Neonatal intrahepatic cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic cholestasis [PFIC] group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes. Results: The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow-up of TNC patients was 44 months (12 months-168 months). At presentation, hepatobiliary-injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non-null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan-Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study. Conclusions: Neonatal cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non-null PPV or with liver BSEP expression.

Identification of ABCC5 Among ATP-Binding Cassette Transporter Family as a New Biomarker for Hepatocellular Carcinoma Based on Bioinformatics Analysis

“…For instance, mutations in the ABCA4 gene contribute to Stargardt macular degeneration, progressive familial intrahepatic cholestasis is caused by ABCB11 deficiency, and ABCC7, which is also known as cystic fibrosis transmembrane conductance regulator, is linked to cystic fibrosis. [8][9][10] ABC transporters are also involved in absorbing, distributing, and excreting the drugs and their metabolites, 11 which is associated with drug resistance of cancer cells. For example, ABCB1 is confirmed to be involved in multidrug resistance (MDR) and it can also be named MDR.…”

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

“…Patients with BSEP1 genotype (p.D482G and p.E297G) have residual BSEP functionality and thus have a milder phenotype as compared to patients exhibiting BSEP2/BSEP3 genotype. There is wide geographical variations in genotype with the commonest mutations found in a study from Shanghai being c.145C>T (p.Gln49Ter) and c.2594C>T (p.Ala865Val)[ 21 ]. Severe phenotypes are often associated with mutations leading to premature protein truncation or failure of protein production.…”

“…Hence, close monitoring of these children particularly those carrying 2 null mutations is essential[ 22 ]. Children with transient neonatal cholestasis harbour non-null variants, express immune-histochemically detectable BSEP and have better outcomes[ 21 ].…”

Genetics: A new clinical tool for the hepatologist

“…Similarly, Li et al showed that carriers of biallelic non‐null mutations of ABCB11 , encoding for bile salt export protein (BSEP), present more frequently with transient neonatal cholestasis, while patients with more severe mutations have lower BSEP expression and tend to develop progressive FIC type 2 13 …”