Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis

Abstract

Aim: To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others.

Methods: Of 47 patients with neonatal cholestasis, five infants had chronic intrahepatic cholestasis with normal γ-glutamyl transpeptidase. Direct sequencing analyses of ABCB11, including exons and introns, were performed from peripheral blood.

Results: Living donor-liver transplantation was performed in four patients because of rapidly progressive hepatic failure and hepatocellular carcinoma. Three missense mutations were found in two patients: compound heterozygous 677C>T (S226L)/3007G>A (G1003R) and heterozygous 2296G>A (G766R). The mutations were located near and in the transmembranous space.

Conclusion: Alterations in the transmembrane of the bile salt export pump in the Korean infants were different from those previously reported in Chinese, Japanease, Taiwanese, and European patients.

Keywords: ABCB11; Bile salt export pump; Hepatocellular carcinoma; Progressive familial intrahepatic cholestasis.

Figure 1

Radiologic hepatic evaluations in patient 1 and 2. A: Abdominal computed tomography of patient 1 revealed two contrast-enhanced hepatic masses (arrows) at 21 mo of age; B: Gallstone and its posterior shadow (circle) were observed on liver ultrasonography in patient 2.

Figure 2

Liver histologic features from infants with chronic intrahepatic cholestasis with normal ranges of γ-glutamyl transpeptidase. A: Hepatocellular carcinoma was confirmed by liver specimen at hepatectomy taken from patient 1 at 24 mo of age. Cellular atypia with trabecular and acinar type was shown. Microvascular invasion was not identified; hematoxylin-eosin stain, original magnification × 400; B: Electron microscopic examination of liver specimen from patient 2 shows many globular or curly appearance electron dense materials in the cytoplasm with original magnification of × 3.5k; C: Liver biopsy at hepatectomy taken at 6 months of age from patient 3 shows periportal fibrosis, inflammatory cell infiltration, intracanalicular bile plugs, giant cell formation, and bile ductular proliferation; hematoxylin-eosin stain, original magnification × 200; D: Electron microscopic examination of liver specimen from patient 4 at 3.5 mo of age reveals amorphous and coarse granular bile pigments in the dilated bile canaliculi. Original magnification × 5.0k; E: Electron microscopic examination of liver specimen from patient 5 shows aggregated bile pigments in the cytoplasm. Original magnification × 2.5k.

Figure 3

Direct sequencing analysis of the ABCB11 genes demonstrating (A) heterozygous C to T substitution in exon 8 predicting a missense mutation at amino acid position 226(p.S226L) (B) heterozygous G to A in exon 23 predicting a missense mutation at amino acid position 1003 (p.G1003R), and (C) heterozygous G to A in exon 19 predicting a missense mutation at amino acid position 776(p.G776R), (A) and (B) were detected in ABCB11 gene of patient 1 and (C) was detected in patient 2.

Figure 4

Putative secondary structure of bile salt export pump generated with the TOPO program (http://www.sacs.ucsf.edu/TOPO-run/wtopo.pl). Mutations are represented in red for mutations in patient 1 and 2, green for Japanese, blue for Taiwanese, and yellow for common European mutations. Bile salt export pump alterations in the present study were located at and near the transmembranous space, which was different from most of the mutations from Chinese, Japanese, Taiwanese, and European patients[2,5,7,12].