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

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 mu mol/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. Single variants in ABCB4 have a high prevalence in children with cholestatic liver disease. The liver disease is usually mild in the form of hyperbilirubinaemia, cholestasis and cholelithiasis and tends to resolve during childhood. image Carriers of variants in adenosine triphosphate binding cassette subfamily B member 4 (ABCB4) have an increased chance of cholestatic liver disease in adulthood.What is New There is a high prevalence of ABCB4 heterozygosity in children with cholestatic liver disease. In childhood, the liver disease is usually mild and tend to resolve over time.