Clinical and Laboratory Observations
FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low γ-glutamyltranspeptidase levels,☆☆

https://doi.org/10.1067/mpd.2002.119993Get rights and content

Abstract

To elucidate the frequency of FIC1 (ATP8B1) and BSEP (ABCB11) mutations in Taiwanese children with chronic intrahepatic cholestasis with low γ-glutamyltranspeptidase (GGT) levels, we assessed 13 unrelated patients with infantile onset chronic intrahepatic cholestasis. Liver complementary DNA sequencing was performed in 7 infants for mutation analyses of FIC1 and BSEP genes. Two distinct liver histologic features were found. Group 1 (n = 5) was characterized by bland cholestasis and group 2 (n = 8) by giant cell transformation. Group 2 patients were associated with higher transaminase levels, α-fetoprotein levels, and early mortality. Novel FIC1 mutations were found in all 4 patients tested in group 1, including a 74-bp deletion, a 98-bp deletion, a nonsense, and 2 missense mutations. BSEP mutations were found in 2 of the 3 patients in group 2, including 2 missense mutations and a 1-bp deletion. Phenotypic characterization is useful to differentiate FIC1- from BSEP-related disease.(J Pediatr 2002;140:119-24)

Section snippets

Patients

Thirteen patients admitted to the Department of Pediatrics in National Taiwan University Hospital for cholestasis of infancy of unknown etiology fulfilled the following criteria:

  • There was onset of chronic cholestatic liver disease before 12 months of age that lasted for >6 months, or the patient died of the disease during the follow-up period.

  • Serum GGT levels were normal or low (<94 U/L) according to the normal range of infants in our hospital.

  • A thorough search for known cholestasis in infancy

Phenotype characterization

Two distinct histopathologic phenotypes were identified (Table II).

. Clinical, pathologic, and genetic analyses of 13 patients with chronic intrahepatic cholestasis and low GGT levels

Case No.Age at onset/sexSymptomsAge at follow-upOutcomePathologic featuresGenotype
11 mo/FPersistent JD, intractable pruritus, hepatomegaly, mild diarrhea in infancy6 yLiver transplantation at 5.5 yHepatocellular cholestasis, lobular disarray, Byler's bile, cirrhosis at hepatectomyFIC1: heterozygous deletion at

Discussion

FIC1 and BSEP mutations were found in 6 of 7 (86%) Taiwanese children with chronic intrahepatic cholestasis of low GGT type and without a positive family history. All the mutations were different from those reported by patients of Amish, European, or Arabic descent. A higher prevalence of genetic defects in FIC1 and BSEP in previously uncharacterized cholestasis in infants of diverse ethnic backgrounds may be predicted. In children of East Asian background, the frequencies of certain genetic

Acknowledgements

We thank Ming-Tsong Cheng, MD, Hsian-Hung Shih, MD, and Fu-Chen Huang, MD, for referring the patients, Wuh-Liang Hwu, MD, for advice in genetic analysis, Daw-Jen Tsuei, PhD, for technical advice, and Ms Li-Yin Wang for technical assistance.

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    Supported by grants from the National Science Council, Taiwan (NSC 89-2314-B-002-040), and the National Taiwan University Hospital (88N130).

    ☆☆

    Reprint requests: Mei-Hwei Chang, MD, 7F, No. 7, Chung-Shan S Rd, Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.

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