Diagnosis in bile acid-CoA: amino acid N-acyltransferase deficiency

Paediatric Liver Service and Institute of Liver Studies, King's College Hospital, London SE5 9RS, United Kingdom.
World Journal of Gastroenterology (Impact Factor: 2.37). 07/2012; 18(25):3322-6. DOI: 10.3748/wjg.v18.i25.3322
Source: PubMed


Cholate-CoA ligase (CCL) and bile acid-CoA: amino acid N-acyltransferase (BAAT) sequentially mediate bile-acid amidation. Defects can cause intrahepatic cholestasis. Distinction has required gene sequencing. We assessed potential clinical utility of immunostaining of liver for CCL and BAAT. Using commercially available antibodies against BAAT and CCL, we immunostained liver from an infant with jaundice, deficiency of amidated bile acids, and transcription-terminating mutation in BAAT. CCL was normally expressed. BAAT expression was not detected. Immunostaining may facilitate diagnosis in bile-acid amidation defects.

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Available from: Peter T Clayton, Sep 30, 2015
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    • "Errors in synthesis of bile acids may lead to hepatic cholestasis that is usually diagnosed in children [5]. Diagnosis of a bile acid amidation defect in a child by immunohistochemistry has been reported [6]. An earlier report on a child with hypocalcemic convulsions, rickets, and epistaxis due to secondary vitamin K deficiency showed the difficulty with direct detection of bile acid abnormalities in serum and urine. "
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    ABSTRACT: Patient: Female, 70 Final Diagnosis: Bile acid amino transferase deficiency Symptoms: Headache • indigestion • itching skin • nausea • vomiting Medication: - Clinical Procedure: - Specialty: Gastroenterology and Hepatology. Challenging differential diagnosis. Bile acid synthesis impairments are difficult to diagnose due to non-specific manifestations related to progressive failure to absorb essential fatty acids and fat soluble vitamins and failure to maintain normal intestinal microbiota. A 70-year-old female presented with long-standing history of recurrent headaches, indigestion, dry, scaly, itching skin, and fluid around knee joints. Quantitative Electroencephalography (QEEG) revealed widespread excess theta maximum in the temporal regions. A rare pattern of elevated plasma glycine and taurine led to suspicion of BAATD. A stool profile employing molecular probes for commensal bacteria revealed elevation of Fusobacteria spp. Implementation of bile acid replacement therapy (BART) produced rapid remission of headache and other symptoms and a three-month follow up stool profile revealed normalization of fecal Fusobacteria populations that remained normal after one year of BART. QEEG analyses 4 weeks following BART showed evidence of significant improvement in CNS functioning. This case illustrates the potential for diagnosis of latent, adult BAATD by finding a unique pattern of plasma amino acids and monitoring of therapy by observing normalization of fecal commensal bacteria and functional brain assessments.
    American Journal of Case Reports 02/2014; 15:63-8. DOI:10.12659/AJCR.889906
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    • "Three of these four genes are related to BA metabolism and are targets of Fxr/Nr1h4 [2]. Moreover, mutations in Baat, Abcg5 or Abcg8 have been shown to be involved in the development of cholestasis in humans [2,8]. Although Klf15 is not a Fxr target, it is known to be involved in gluconeogenesis [27], which is regulated by Fxr [28,29]. "
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    ABSTRACT: Unexpected cholestasis substantially contributes to drug failure in clinical trials. Current models used for safety assessment in drug development do not accurately predict cholestasis in humans. Therefore, it is of relevance to develop new screening models that allow identifying drugs with cholestatic properties. We employed mouse precision cut liver slices (PCLS), which were incubated 24 h with two model cholestatic compounds: cyclosporin A (CsA) and chlorpromazine (CPZ). Subsequently, transcriptome analysis using DNA microarrays and q-PCR were performed to identify relevant biological processes and biomarkers. Additionally, histology was carried out and levels of triglycerides (TG) and bile acids (BA) were measured. To verify the ex vivo mouse data, these were compared with publically available human data relevant for cholestasis. Whole genome gene expression analysis showed that CsA up-regulated pathways related to NF-kappaB, ER stress and inflammation. Both CsA and CPZ down-regulated processes related to extracellular matrix (ECM) remodelling, BA homeostasis, Fxr signalling, and energy metabolism. The differential expression of a number of characteristic genes (e.g. Abcg5, Abcg8, Klf15, and Baat) could be confirmed by q-PCR. Histology revealed that CsA but not CPZ induced "ballooning" of hepatocytes. No effects on TG and BA levels were observed after incubation of PCLS with CsA and CPZ. A substantial number of processes altered in CsA- and CPZ-treated mouse PCLS ex vivo was also found to be affected in liver biopsies of cholestatic patients. The present study demonstrated that mouse PCLS can be used as a tool to identify mechanisms of action of cholestatic model compounds. The induction of general stress responses and down-regulated Fxr signalling could play a role in the development of drug induced cholestasis. Importantly, comparative data analysis showed that the ex vivo mouse findings are also relevant for human pathology. Moreover, this work provides a set of genes that are potentially useful to assess drugs for cholestatic properties.
    BMC Medical Genomics 10/2013; 6(1):39. DOI:10.1186/1755-8794-6-39 · 2.87 Impact Factor
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    ABSTRACT: 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 μmol/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.
    Gastroenterology 02/2013; 144(5). DOI:10.1053/j.gastro.2013.02.004 · 16.72 Impact Factor
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