Clinical phenotype of adult‐onset liver disease in patients with variants in ABCB4 , ABCB11 , and ATP8B1

Abstract

Variants in ATP8B1, ABCB11, and ABCB4 underlie the most prevalent forms of progressive familial intrahepatic cholestasis. We aim to describe variants in these genes in a cohort of patients with adult-onset liver disease, and explore a genotype-phenotype correlation. Patients with onset of liver disease aged above 18 who underwent sequencing of cholestasis genes for clinical purposes over a 5-year period were identified. Bioinformatic analysis of variants was performed. Liver histology was evaluated in patients with variants.Of the 356 patients tested, at least one variant was identified in 101 (28.4%): 46 ABCB4, 35 ABCB11, and 28 ATP8B1. Patients with ABCB4 variants had chronic liver disease (71.7%) and pregnancy-associated liver dysfunction (75%), with a younger age of onset in more severe genotypes (p = 0.046).ABCB11 variants presented with pregnancy-associated liver dysfunction (82.4%) and acute/episodic cholestasis (40%), with no association between age of onset and genotype severity. ATP8B1 variants were associated with chronic liver disease (75%); however, they were commonly seen in patients with an alternate etiology of liver disease and variants were of low predicted pathogenicity. In adults with suspected genetic cholestasis, variants in cholestasis genes were frequently identified and were likely to contribute to the development of liver disease, particularly ABCB4 and ABCB11. Variants were often in heterozygous state, and they should no longer be considered recessive Mendelian traits. Sequencing cholestasis genes in selected patients with adult-onset disease should be considered, with interpretation in close collaboration with histopathologists and geneticists.

Diagnostic workup of suspected hereditary cholestasis in adults: a case report

“…Vasor results in a value of 0.89 for p.(Asn489Tyr) and therefore predicts the variant to be probably pathogenic (0 = benign, 1 = pathogenic) which is in line with the clinical findings in the presented LPAC patient and another patient from our cohort with gallstone disease and the respective MDR3 variant. Heterozygous variants of unknown significance (VUS) are potentially relevant for a cholestatic phenotype and malignancy risk [12,23,[48][49][50][51].…”

Recurrent Abdominal Pain After Cholecystectomy: Low Phospholipid-Associated Cholelithiasis

“…Heterozygous or monoallelic variants are more common and account for the attenuated presentations of cholestatic syndromes such as ICP, drug-induced liver injury, and LPAC. [3][4][5] In contrast, the homozygous, or biallelic variants correlate with a more severe loss of MDR3 function and the classic PFIC3 presentation, with jaundice, pruritus, hepatosplenomegaly, cirrhosis, portal hypertension, and growth/ mental retardation occurring in early childhood. 3,5,6 In a large case-control study in France, it was estimated that LPAC represents approximately 1% of symptomatic cholelithiasis in adults admitted to nonacademic healthcare centers for symptomatic gallstone disease.…”

Hepatic Dry Copper Weight in Pediatric Autoimmune Liver Disease

“…PFIC are a group of disorders characterized by severe early onset cholestasis, and elevated hepatic dry copper weight has been reported as a result of secondary copper overload from cholestasis in patients with PFIC3 (MDR3 deficiency) and ABCB4 variants (17–19). Although elevated tissue copper has not been described in ABCB4 heterozygous patients, they may have reduced functional MDR3 protein and can develop chronic cholestatic liver disease (20). It is therefore possible that the genetic variants in these patients have contributed to their elevated tissue copper.…”