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Chinese Children With Chronic Intrahepatic Cholestasis and High γ-Glutamyl Transpeptidase: Clinical Features and Association With ABCB4 Mutations

Fang, Ling-Juan*; Wang, Xiao-Hong*; Knisely, A.S.; Yu, Hui*; Lu, Yi*; Liu, Li-Yan*; Wang, Jian-She*

Journal of Pediatric Gastroenterology & Nutrition: August 2012 - Volume 55 - Issue 2 - p 150–156
doi: 10.1097/MPG.0b013e31824ef36f
Original Articles: Hepatology and Nutrition

Objective: The aims of the present study was to study the significance of ABCB4 mutations in mainland Chinese children with chronic intrahepatic cholestasis and to correlate genetic findings with clinical features and response to ursodeoxycholic acid (UDCA) therapy.

Methods: Thirteen patients with chronic intrahepatic cholestasis and elevated serum γ-glutamyl transpeptidase activity of unknown cause were enrolled in a single pediatric center. All of the encoding exons and flanking areas of ABCB4 were sequenced. Available liver biopsy specimens were immunostained for multidrug resistance protein 3. The clinical features, biochemical parameters, and responses to therapy were compared with patients with or without ABCB4 mutation(s).

Results: Six different ABCB4 mutations were identified in 3 patients; each patient was a compound heterozygote. Apart from c.139C>T (p.R47X), all were novel, including c.344+2_+3insT, c.1376A>G (p.D459G), c.1745G>A (p.R582Q), c.2077_2078delC (p.P693HfsX698), and c.3825_3826delA (p.M1276WfsX1308). Absent or reduced multidrug resistance protein 3 canalicular immunostaining was demonstrated in patients with ABCB4 mutations. Serum total bile acid levels were higher in patients with ABCB4 mutations than in patients without ABCB4 mutations (352.5 ± 97.0 vs 55.9 ± 50.4 μmol/L, P = 7.32E-05). There was no difference in other biochemical parameters between patients with and without ABCB4 mutations. After oral UDCA administration in 3 patients with ABCB4 mutations, pruritus disappeared, growth improved, spleen size decreased, and platelet counts increased. In the 10 patients without ABCB4 mutations, an inconsistent response to UDCA therapy was observed.

Conclusions: In mainland Chinese children, some cases of chronic intrahepatic cholestasis with high γ-glutamyl transpeptidase could be attributed to ABCB4 mutations. UDCA administration partially improved clinical symptoms and liver function.

*Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China

Institute of Liver Studies, King's College Hospital Denmark Hill, London, UK.

Address correspondence and reprint requests to Jian-She Wang, Center for Pediatric Liver Disease, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai 201102, China (e-mail:

Received 17 August, 2011

Accepted 6 February, 2012

The present study received support from National Natural Science Foundation of China, grant no. 81070281.

The authors report no conflicts of interest.

© 2012 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,