Diagnostic Value of Serum γ-Glutamyl Transpeptidase Activity in Liver Diseases in Children

Maggiore, Giuseppe; Bernard, Olivier; Hadchouel, M; Lemonnier, A; Alagille, D

doi:10.1097/00005176-199101000-00005

Cited by 96 publications

(41 citation statements)

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“…Liver histology often reveals fibrosis with portal inflammation and strong bile duct proliferation in an early stage. 16 A characteristic high-serum gamma-glutamyltransferase activity is found in PFIC3. As a consequence of the cirrhosis, the PFIC3 patients are prone to gastrointestinal bleeding.…”

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confidence: 98%

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

et al. 2011

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The wide clinical spectrum of the ABCB4 gene (ATP-binding cassette subfamily B member 4) deficiency syndromes in humans includes low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptivesinduced cholestasis (CIC), and progressive familial intrahepatic cholestasis type 3 (PFIC3). No ABCB4 mutations are found in a significant proportion of patients with these syndromes. In the present study, 102 unrelated adult patients with LPAC (43 patients) or CIC/ICP (59 patients) were screened for ABCB4 mutations using DNA sequencing. Heterozygous ABCB4 point or short insertion/deletion mutations were found in 37% (16/43) of the LPAC patients and in 27% (16/59) of the ICP/CIC patients. High-resolution gene dosage methodologies were used in the 70 negative patients. Here, we describe for the first time ABCB4 partial or complete heterozygous deletions in 7% (3/43) of the LPAC patients, and in 2% (1/59) of the ICP/CIC patients. Our observations urge to systematically test patients with LPAC, ICP/CIC, and also children with PFIC3 for the presence of ABCB4 deletions using molecular tools allowing detection of gross rearrangements. In clinical practice, a comprehensive ABCB4 alteration-screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing. An early diagnosis of these biliary diseases may be beneficial because of the preventive effect of ursodeoxycholic acid on biliary complications. Further comparative studies of patients with well-characterized genotypes (including deletions) and phenotypes will help determine whether ABCB4 mutation types influence clinical outcomes.

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confidence: 98%

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

et al. 2011

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“…Patients with bile salt synthesis defects and Byler patients have normal serum ␥-glutamyltransferase (␥-GT) levels (21). A third type of PFIC patients can be distinguished from the other two types by a high serum ␥-GT activity and liver histology that shows portal inflammation and ductular proliferation in an early stage (21,22). These differences suggest that a distinct etiological mechanism underlies this third type of PFIC.…”

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confidence: 99%

Mutations in the MDR 3 gene cause progressive familial intrahepatic cholestasis

Vree

Jacquemin

Sturm

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

698

449

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Class III multidrug resistance (MDR) Pglycoproteins (P-gp), mdr2 in mice and MDR3 in man, mediate the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte. Mice with a disrupted mdr2 gene completely lack biliary phospholipid excretion and develop progressive liver disease, characterized histologically by portal inf lammation, proliferation of the bile duct epithelium, and fibrosis. This disease phenotype is very similar to a subtype of progressive familial intrahepatic cholestasis, hallmarked by a high serum ␥-glutamyltransferase (␥-GT) activity. We report immunohistochemistry for MDR3 P-gp, reverse transcription-coupled PCR sequence analysis, and genomic DNA analysis of MDR3 from two progressive familial intrahepatic cholestasis patients with high serum ␥-GT. Canalicular staining for MDR3 P-gp was negative in liver tissue of both patients. Reverse transcriptioncoupled PCR sequencing of the first patient's sequence demonstrated a homozygous 7-bp deletion, starting at codon 132, which results in a frameshift and introduces a stop codon 29 codons downstream. The second patient is homozygous for a nonsense mutation in codon 957 (C 3 T) that introduces a stop codon (TGA). Our results demonstrate that mutations in the human MDR3 gene lead to progressive familial intrahepatic cholestasis with high serum ␥-GT. The histopathological picture in these patients is very similar to that in the corresponding mdr2(؊͞؊) mouse, in which mdr2 P-gp deficiency induces complete absence of phospholipid in bile.

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“…In contrast, there is a second group of patients with PFIC who exhibit high serum GGTP levels and bile duct proliferation along with portal inflammatory infiltrates on liver histology. 7 These changes resemble those that have been observed following disruption of the mdr2 gene, the mouse homolog of human MDR3, which encodes a canalicular P-glycoprotein required for biliary phospholipid secretion. 8 In one patient with this second type of PFIC, MDR3 messenger RNA was undetectable and in another phospholipid in bile was markedly reduced.…”

Section: Commentsmentioning

confidence: 62%

What the Amish can tell us about? cholestasis

Moseley

1998

Hepatology

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Cholestasis, or impaired bile flow, is an important but poorly understood manifestation of liver disease. Two clinically distinct forms of inherited cholestasis, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), were previously mapped to 18q21. Haplotype analysis narrowed the candidate region for both diseases to the same interval of less than 1 cM, in which we identified a gene mutated in BRIC and PFIC1 patients. This gene (called FIC1) is the first identified human member of a recently described subfamily of P-type ATPases; ATP-dependent aminophospholipid transport is the previously described function of members of this subfamily. FIC1 is expressed in several epithelial tissues and, surprisingly, more strongly in small intestine than in liver. Its protein product is likely to play an essential role in enterohepatic circulation of bile acids; further characterization of FIC1 will facilitate understanding of normal bile formation and cholestasis. ABSTRACTClass III multidrug resistance (MDR) P-glycoproteins (P-gp), mdr2 in mice and MDR3 in man, mediate the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte. Mice with a disrupted mdr2 gene completely lack biliary phospholipid excretion and develop progressive liver disease, characterized histologically by portal inflammation, proliferation of the bile duct epithelium, and fibrosis. This disease phenotype is very similar to a subtype of progressive familial intrahepatic cholestasis, hallmarked by a high serum ␥-glutamyltransferase (␥-GT) activity. We report immunohistochemistry for MDR3 P-gp, reverse transcription-coupled PCR sequence analysis, and genomic DNA analysis of MDR3 from two progressive familial intrahepatic cholestasis patients with high serum ␥-GT. Canalicular staining for MDR3 P-gp was negative in liver tissue of both patients. Reverse transcrip-

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Diagnostic Value of Serum γ-Glutamyl Transpeptidase Activity in Liver Diseases in Children

Cited by 96 publications

References 0 publications

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

Mutations in the MDR 3 gene cause progressive familial intrahepatic cholestasis

What the Amish can tell us about? cholestasis

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