Clinical and Laboratory ObservationsFIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low γ-glutamyltranspeptidase levels☆,☆☆
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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).Case No. Age at onset/sex Symptoms Age at follow-up Outcome Pathologic features Genotype 1 1 mo/F Persistent JD, intractable pruritus, hepatomegaly, mild diarrhea in infancy 6 y Liver transplantation at 5.5 y Hepatocellular cholestasis, lobular disarray, Byler's bile, cirrhosis at hepatectomy FIC1: 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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Whole-Genome Sequencing Reveals Large ATP8B1 Deletion/Duplications as Second Mutations Missed by Exome-Based Sequencing
2021, Journal of Molecular DiagnosticsAnimal models to study bile acid metabolism
2019, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Studies of Dutch and Amish patients revealed that BRIC type 1 (BRIC1) and PFIC type 1 (PFIC1) are caused by mutations in ATP8B1 [168]. As compared to patients with BSEP mutations, patients with ATP8B1-deficiency typically presents with somewhat milder liver damage, but also extrahepatic complications, such as secretory diarrhea, pancreatitis and hearing loss, which are not alleviated by liver transplantation [204–206]. In 2004, mice were generated that are homozygous for the ATP8B1 G308V point mutation, which had been reported in Amish PFIC patients [98,168].
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2018, EBioMedicineCitation Excerpt :However, approximately one-third of individuals with normal-GGT PFIC do not have mutations in ATP8B1 or ABCB11 (Davit-Spraul et al., 2010; Klomp et al., 2004) and mutations in TJP2 seem not to explain all of the remaining patients (Sambrotta et al., 2014). Moreover, in some patients with normal-GGT PFIC, genome sequencing detects a mutation in only one allele of ATP8B1 or ABCB11 or identifies mutations in either gene that are difficult to distinguish as disease-causing mutations or rare normal variants (Chen et al., 2002; Davit-Spraul et al., 2010; Klomp et al., 2004; Liu et al., 2007; Matte et al., 2010). This, together with the fact that individuals with normal-GGT PFIC share many clinical features (Davit-Spraul et al., 2009), makes the determination of the subtypes of PFIC more complex.
ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population
2013, Digestive and Liver DiseaseThe bile salt export pump (BSEP) in health and disease
2012, Clinics and Research in Hepatology and Gastroenterology
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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).
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Reprint requests: Mei-Hwei Chang, MD, 7F, No. 7, Chung-Shan S Rd, Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.