The ABCB4 p.T175A variant as potential modulator of hepatic fibrosis in patients with chronic liver diseases: Looking beyond the cholestatic realm
Authors: Marcin Krawczyk, Monika Rau, Frank Grünhage, Jörn M. Schattenberg, Heike Bantel, Anita Pathil, Münevver Demir, Johannes Kluwe, Tobias Boettler, Andreas Geier, Frank Lammert
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Schattenberg consults for Genfit and advises Intercept. Supported, in part, by Saarland University (HOMFOR program). Author names in bold designate shared co‐first authorship. To the editor: With great interest we have read the manuscript by Delaunay et al.1 introducing the first classification of cholestatic ABCB4 (hepatocanalicular phosphatidylcholine translocator) variants. In brief, the authors investigated a total of 12 frequent ABCB4 variants and, based on their functional effects, categorized them in five different classes. Among these, one of the “variants with no detectable effects”, p.T175A,1 came to our attention. Of note, a large‐scale, population‐based whole‐genome sequencing study2 demonstrated a novel association between the common cholestatic ABCB4 polymorphism c.711A>T and liver cirrhosis. To expand on these observations,1 we assessed the effects of the ABCB4 p.T175A mutation and the c.711A>T polymorphism on liver fibrosis in two large independent cohorts of patients. The first transient elastography–based cohort comprised 678 patients (age 50 ± 13 years, 414 men, 150 biopsied)3 with chronic liver diseases. The second cohort was composed of 515 patients with nonalcoholic fatty liver disease (age 48 ± 13 years, 235 men, 320 biopsied).4 In a total of 1,193 genotyped participants, 30 patients carried the p.T175A variant, whereas the procholestatic c.711A allele was present in the majority of patients (n = 796). Figure 1 illustrates that in the first cohort, carriers of the p.T175A variant presented with significantly (P = 0.02) increased liver stiffness in comparison to patients with the wild‐type genotype. Among five biopsied carriers of the risk allele, three displayed fibrosis stage F4. In the nonalcoholic fatty liver disease cohort, seven of nine carriers of the p.T175A risk allele (78%) were scheduled for liver biopsy; the variant was, however, not significantly associated with histological fibrosis stage. Interestingly, we detected significantly (P = 0.03) increased liver stiffness among carriers of the cholestatic ABCB4 c.711 allele, but this effect was apparent only in patients who also carried the common profibrogenic PNPLA3 (adiponutrin) p.I148M risk allele (n = 315).3Figure 1: Patients with chronic liver diseases carrying the ABCB4 p.T175A risk allele (n = 21) present with significantly higher median transient elastography levels than individuals with the wild‐type genotype. Abbreviation: TE, transient elastography.Based on these results, we reckon that, even if the ABCB4 variant p.T175A does not seem to alter the function of the translocator directly,1 its carriers might develop progressive liver injury and fibrosis. Hence, we speculate that the ABCB4 variants categorized by Delaunay et al.1 might contribute to more severe liver phenotypes, also beyond cholestasis; however, some of these associations are restricted to selected populations. Because the effects of potentially profibrogenic variants might not be apparent when adjudicating liver fibrosis in biopsy specimens, we and others have advocated a wider use of elastography for integrated assessment of pathogenic pathways in patients with chronic liver diseases.