Normal serum γ-glutamyl-transpeptidase activity identifies groups of infants with idiopathic cholestasis with poor prognosis

Maggiore, Giuseppe; Bernard, Olivier; Riely, Caroline A.; Hadchouel, Michelle; Lemonnier, A; Alagille, D

doi:10.1016/s0022-3476(87)80079-3

Cited by 82 publications

(47 citation statements)

References 5 publications

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“…The infant, a 10-wk-old Mexican offspring of a first cousin marriage presented with progressive jaundice, elevated concentrations of serum liver enzymes, and a prolonged prothrombin time due in part to vitamin K malabsorption. Interestingly, there was a normal serum ␥-glutamyltranspeptidase concentration, which has been shown previously to be highly associated with, although not exclusive to, patients with inborn errors in bile acid synthesis (59), since it is also a feature of Byler's disease, a condition of progressive familial intrahepatic cholestasis (60)(61)(62). A liver biopsy and histological analysis revealed diffuse syncytial giant cell transformation of hepatocytes with associated bile ductule proliferation and fibrosis (Fig.…”

Section: Discussionmentioning

confidence: 61%

Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

Setchell¹,

Schwarz²,

O'Connell³

et al. 1998

J. Clin. Invest.

339

247

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We describe a metabolic defect in bile acid synthesis involving a deficiency in 7 ␣ -hydroxylation due to a mutation in the gene for the microsomal oxysterol 7 ␣ -hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3 ␤ -hydroxy-5-cholenoic and 3 ␤ -hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were Ͼ 4,500 times normal. The biochemical findings were consistent with a deficiency in 7 ␣ -hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7 ␣ -hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon.

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Section: Discussionmentioning

confidence: 61%

Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

Setchell¹,

Schwarz²,

O'Connell³

et al. 1998

J. Clin. Invest.

339

247

View full text Add to dashboard Cite

show abstract

“…The human gene for GGT has been mapped to chromosome 22q11 [7]. Historically, it has been noted that patients diagnosed with INH and in whom there is positive family history of neonatal hepatitis or low levels of GGT have progressed to chronic liver disease [14]. Newer diagnostic entities, such as progressive familial intrahepatic cholestasis (PFIC) types 1 and 2, inborn errors of bile acid synthesis, arthrogryposis-renal dysfunctioncholestasis (ARC) syndrome and lymphedema-cholestasis (LCS or Aegenes) syndrome, now account for some of these patients.…”

Section: Introductionmentioning

confidence: 99%

Significance of low or normal serum gamma glutamyl transferase level in infants with idiopathic neonatal hepatitis

2006

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“…Two loci for Byler have been found and mapped to chromosome 18q21-q22 (19) and recently to chromosome 2 (20). 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).…”

mentioning

confidence: 99%

“…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.…”

mentioning

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.

Self Cite

703

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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Normal serum γ-glutamyl-transpeptidase activity identifies groups of infants with idiopathic cholestasis with poor prognosis

Cited by 82 publications

References 5 publications

Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

Significance of low or normal serum gamma glutamyl transferase level in infants with idiopathic neonatal hepatitis

Mutations in the MDR 3 gene cause progressive familial intrahepatic cholestasis

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