ABCB4 deficiency is causative for hepatic copper accumulation in a patient with features of Wilson Disease

Abstract

Clinical Case: A 21-year-old patient presented with mild pruritus and elevated liver enzymes (ALT 181 U/L; AST 106 U/L; γ-GT 212 U/L; AP 220 U/L). Of note, his sister had been diagnosed for Wilson Disease (WD) before. Comprehensive work-up provided no evidence of viral or autoimmune liver disease, primary biliary cirrhosis or sclerosing cholangitis. 24-hour urinary copper excretion was increased (101µmol/day), however, with normal serum copper and coeruloplasmin levels. Kayser-Fleischer rings were not detectable. Liver histology was compatible with chronic hepatitis with mild portal and parenchymal inflammation, mild fibrosis, increased copper staining and regular bile ducts. Quantitative analysis revealed elevated hepatic copper content (102µg/g dry weight). Thus, a diagnosis of probable WD was entertained and chelation therapy started. However, there was no biochemical response and sequencing of the ATP7B gene yielded unremarkable results. Given the histological findings and positive family history, sequencing of the hepatocanalicular phospholipid transporter ABCB4 was carried out revealing a heterozygous mutation (c.139C>T; p.Arg47X). In addition, a second heterozygous mutation (c.959C>T; p.Ser320Phe) was detected previously described in progressive familial cholestasis type 3 (PFIC3). Ursodeoxycholic acid was started with significant biochemical improvement. Discussion: Variable degrees of secondary copper overload have been appreciated in common cholestatic disorders e.g. PBC or PSC. However, adult ABCB4 deficiency with a PFIC3-like phenotype underlying significant hepatic copper deposition with challenging differentiation from WD has only rarely been reported.(1,2) Whether or not ABCB4 plays an active role in hepatic copper homeostasis beyond alterations in cholestasis-related copper excretion is unknown. The reported clinical case underscores the potential of dedicated genetic testing in the clinical assessment of hereditary cholestatic disorders. Literatur: 1. Anheim et al. Clin Genet 2010 2. Ramraj et al. Hepatology 2010