Genetic Defects in Bile Acid Conjugation Cause Fat-Soluble Vitamin Deficiency

被引:74
作者
Setchell, Kenneth D. R. [1 ]
Heubi, James E. [2 ]
Shah, Sohela [3 ,4 ]
Lavine, Joel E. [7 ]
Suskind, David [8 ,9 ]
Al-Edreesi, Mohammed [10 ]
Potter, Carol [11 ]
Russell, David W. [12 ]
O'Connell, Nancy C. [1 ]
Wolfe, Brian [1 ]
Jha, Pinky [1 ]
Zhang, Wujuan [1 ]
Bove, Kevin E. [1 ]
Knisely, Alex S. [13 ]
Hofmann, Alan F. [14 ]
Rosenthal, Philip [3 ,4 ,5 ,6 ]
Bull, Laura N. [3 ,4 ]
机构
[1] Childrens Hosp Med Ctr, Dept Pathol & Lab Med, Cincinnati, OH USA
[2] Childrens Hosp Med Ctr, Div Gastroenterol & Nutr, Cincinnati, OH USA
[3] Univ Calif San Francisco, Med Ctr, UCSF Liver Ctr Lab, San Francisco, CA USA
[4] Univ Calif San Francisco, Med Ctr, Inst Human Genet, San Francisco, CA USA
[5] Univ Calif San Francisco, Med Ctr, Dept Pediat, San Francisco, CA USA
[6] Univ Calif San Francisco, Med Ctr, Dept Surg, San Francisco, CA USA
[7] Columbia Univ, Morgan Stanley Childrens Hosp, Dept Gastroenterol Hepatol & Nutr, New York, NY USA
[8] Seattle Childrens Hosp, Dept Gastroenterol & Hepatol, Seattle, WA USA
[9] Univ Washington, Med Sch Med, Seattle, WA 98195 USA
[10] Dhahran Hlth Ctr, Pediat Specialty Serv Div, Dhahran, Saudi Arabia
[11] Ohio State Univ, Nationwide Childrens Hosp, Dept Gastroenterol & Nutr, Columbus, OH 43210 USA
[12] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA
[13] Kings Coll Hosp London, Inst Liver Studies, London SE5 8RX, England
[14] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA
基金
美国国家卫生研究院;
关键词
Chronic Liver Disease; Hepatic; Inherited; Nutrient; N-ACYLTRANSFERASE; INBORN ERROR; DIAGNOSIS; IDENTIFICATION;
D O I
10.1053/j.gastro.2013.02.004
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: The final step in bile acid synthesis involves conjugation with glycine and taurine, which promotes a high intraluminal micellar concentration to facilitate lipid absorption. We investigated the clinical, biochemical, molecular, and morphologic features of a genetic defect in bile acid conjugation in 10 pediatric patients with fat-soluble vitamin deficiency, some with growth failure or transient neonatal cholestatic hepatitis. METHODS: We identified the genetic defect that causes this disorder using mass spectrometry analysis of urine, bile, and serum samples and sequence analysis of the genes encoding bile acid-CoA:amino acid N-acyltransferase (BAAT) and bile acid-CoA ligase (SLC27A5). RESULTS: Levels of urinary bile acids were increased (432 +/- 248 mu mol/L) and predominantly excreted in unconjugated forms (79.4% +/- 3.9%) and as sulfates and glucuronides. Glycine or taurine conjugates were absent in the urine, bile, and serum. Unconjugated bile acids accounted for 95.7% +/- 5.8% of the bile acids in duodenal bile, with cholic acid accounting for 82.4% +/- 5.5% of the total. Duodenal bile acid concentrations were 12.1 +/- 5.9 mmol/L, which is too low for efficient lipid absorption. The biochemical profile was consistent with defective bile acid amidation. Molecular analysis of BAAT confirmed 4 different homozygous mutations in 8 patients tested. CONCLUSIONS: Based on a study of 10 pediatric patients, genetic defects that disrupt bile acid amidation cause fat-soluble vitamin deficiency and growth failure, indicating the importance of bile acid conjugation in lipid absorption. Some patients developed liver disease with features of a cholangiopathy. These findings indicate that patients with idiopathic neonatal cholestasis or later onset of unexplained fat-soluble vitamin deficiency should be screened for defects in bile acid conjugation.
引用
收藏
页码:945 / +
页数:17
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