High frequency of ABCB4 and ABCB11 gene variants in adult patients with idiopathic chronic or recurrent cholestasis

Background: Several genes encoding proteins essential for normal bile production have been associated with progressive familial intrahepatic cholestasis in children, but there are few studies evaluating the frequency of variants in these genes among adults with chronic cholestatic disease. The aim of this study was to assess frequency of variants in progressive familial intrahepatic cholestasis–associated genes in adults with idiopathic or episodic cholestatic chronic liver disease (cCLD). Methods: Patients with cCLD of unknown cause followed in 4 different reference centers in Brazil were genotyped for ABCB11 , ABCB4 , ABCC2 , ATP8B1 , CFTR , JAG1 , KIF12 , LSR , MYO5B , NR1H4 , PPM1F , SERPINA1 , TJP2 , USP53 , VIPAS39 , VPS33B , PEX26 , and WDR83OS gene variants using Illumina platforms. Primary biliary cholangitis, primary sclerosing cholangitis, and other causes of cCLD were excluded. Results: Sixty-five patients (40 females; mean±SD age at disease onset, 26.8±13.4 y) were included. Most (65%) had either a family history of cholestatic liver disease or previous signs and symptoms of intrahepatic cholestasis of pregnancy or low phospholipid–associated cholelithiasis. Fifty-seven (88%) had cCLD, whereas 8 (12%) reported recurrent episodic cholestasis. Some had evidence at diagnosis of cirrhosis (n=20) or hepatocellular carcinoma (n=2) or had undergone liver transplantation (n=10). Sequencing revealed 28 variants in ABCB4 (n=25) and ABCB11 (n=3) genes in 42 patients [65%; heterozygous (n=31), homozygous (n=4), and compound heterozygous (n=7)]. Only 17 (61%) were previously reported. Most variants (57%) were classified as pathogenic or likely pathogenic. Conclusions: More than half of the patients with cCLD of unknown cause exhibited pathogenic or likely pathogenic variants in bile transporter genes, particularly ABCB4 . Genotyping may identify most of those patients as late-onset patients with multidrug resistance protein 3 deficiency.