Clinical outcomes of ABCB4 heterozygosity in infants and children with cholestatic liver disease

Abstract

ObjectivesBiallelic variants in the adenosine triphosphate binding cassette subfamily B member 4 (ABCB4) gene which encodes the multidrug resistance 3 protein (MDR3) leads to progressive familiar intrahepatic cholestasis type 3. However, monoallelic variants are increasingly recognized as contributing to liver disease in adults. Our aim was to describe the clinical characteristics of MDR3 heterozygous variants in a large cohort of infants and children with cholestatic liver disease.MethodsThe clinical and genotypic data on pediatric patients seen at King's College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed.ResultsNinety‐two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty‐two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease.ConclusionsRare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.

UK guideline on the transition and management of childhood liver diseases in adulthood

“…132,134 Severe presentations of early-onset childhood disease mainly have biallelic variants in ABCB4, while heterozygotes can present with a milder phenotype that may resolve during childhood. 135,136 There is a genotype-phenotype correlation in adult-onset disease, which can present with either biallelic variants (which are often of milder severity or variants of unknown significance) or heterozygotes. 104,132 Treatment with UDCA to reduce the detergent nature of bile can be commenced however there are limitations to its efficacy.…”

Two novel intronic mutations in ABCB4 gene: clinical manifestations and molecular mechanisms and literatures review

“…The clinical and molecular genetic data of 28 patients, who were de nitely diagnosed with ABCB4 intron variants and had relatively complete clinical information in 10 o cial literatures [4][5][6][11][12][13][14][15][16][17], were summarized in supplemental table 1.…”