Early detection is the most effective way to improve the clinical outcome of biliary atresia (BA). Emerging metabolomics provides a powerful platform for discovering novel biomarkers and biochemical pathways to improve early diagnosis. The aim of this study is to find the potential biomarkers to distinguish BA from neonatal hepatitis syndrome (NHS) by using a metabolomics method. We comprehensively analyzed the serum metabolites in a total of 124 blood samples from patients with BA or neonatal hepatitis syndrome (NHS) and from normal individuals using advanced metabolomic approaches, and found that the levels of glutarylcarnitine (C5DC) significantly increased in the BA group while the levels of threonine (Thr) significantly rose in the NHS group comparing with the other groups. The levels of glutamic acid (Glu) in the BA group were significantly elevated compared to those in the NHS group, but still lower than the hyperbilirubinemia and normal controls. The levels of propionyl carnitine (C3), isovaleryl carnitine (C5) and glutamine (Gln) were reduced in the BA group compared to those in the NHS group, but still higher than the hyperbilirubinemia and normal controls. This study demonstrates the possibility of metabolomics as non-invasive biomarkers for the early detection of BA and also provides new insight into pathophysiologic mechanisms for BA.
References
[1]
Hartley JL, Davenport M, Kelly DA (2009) Biliary atresia. Lancet 374: 1704–1713.
Moore SW, Zabiegaj-Zwick C, Nel E (2012) Problems related to CMV infection and biliary atresia. S Afr Med J 102: 890–892.
[5]
Szavay PO, Leonhardt J, Czech-Schmidt G, Petersen C (2002) The role of reovirus type 3 infection in an established murine model for biliary atresia. Eur J Pediatr Surg 12: 248–250.
[6]
Mack CL, Feldman AG, Sokol RJ (2012) Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis 32: 307–316.
[7]
Baumann U, Ure B (2012) Biliary atresia. Clin Res Hepatol Gastroenterol 36: 257–259.
[8]
Kianifar HR, Tehranian S, Shojaei P, Adinehpoor Z, Sadeghi R, et al. (2013) Accuracy of hepatobiliary scintigraphy for differentiation of neonatal hepatitis from biliary atresia: systematic review and meta-analysis of the literature. Pediatr Radiol (43) 905–919.
[9]
Yang JG, Ma DQ, Peng Y, Song L, Li CL (2009) Comparison of different diagnostic methods for differentiating biliary atresia from idiopathic neonatal hepatitis. Clin Imaging 33: 439–446.
[10]
Dutta M, Joshi M, Srivastava S, Lodh I, Chakravarty B, et al. (2012) A metabonomics approach as a means for identification of potential biomarkers for early diagnosis of endometriosis. Mol Biosyst 8: 3281–3287.
[11]
Wang X, Zhang A, Sun H (2013) Power of metabolomics in diagnosis and biomarker discovery of hepatocellular carcinoma. Hepatology 57: 2072–2077.
[12]
Han X, Rozen S, Boyle SH, Hellegers C, Cheng H, et al. (2011) Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics. PLoS One 6: e21643.
[13]
Noto A, Cibecchini F, Fanos V, Mussap M (2013) NGAL and metabolomics: the single biomarker to reveal the metabolome alterations in kidney injury. Biomed Res Int 2013: 612032.
[14]
Moyer V, Freese DK, Whitington PF, Olson AD, Brewer F, et al. (2004) Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 39: 115–128.
[15]
Esmaili J, Izadyar S, Karegar I, Gholamrezanezhad A (2007) Biliary atresia in infants with prolonged cholestatic jaundice: diagnostic accuracy of hepatobiliary scintigraphy. Abdom Imaging 32: 243–247.
[16]
Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, et al. (2001) Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem 47: 1945–1955.
[17]
Jimenez-Rivera C, Jolin-Dahel KS, Fortinsky KJ, Gozdyra P, Benchimol EI (2013) International incidence and outcomes of biliary atresia. J Pediatr Gastroenterol Nutr 56: 344–354.
[18]
Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, et al. (2006) A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr 148: 467–474.
[19]
Zhang A, Sun H, Wang X (2012) Serum metabolomics as a novel diagnostic approach for disease: a systematic review. Anal Bioanal Chem 404: 1239–1245.
[20]
Zhou K, Lin N, Xiao Y, Wang Y, Wen J, et al. (2012) Elevated bile acids in newborns with Biliary Atresia (BA). PLoS One 7: e49270.
[21]
Mushtaq I, Logan S, Morris M, Johnson AW, Wade AM, et al. (1999) Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry. BMJ 319: 471–477.
[22]
Xu F, Zou L, Liu Y, Zhang Z, Ong CN (2011) Enhancement of the capabilities of liquid chromatography-mass spectrometry with derivatization: general principles and applications. Mass Spectrom Rev 30: 1143–1172.
[23]
Selimoglu MA, Aydogdu S, Yagci RV, Huseyinov A (2001) Plasma and liver carnitine status of children with chronic liver disease and cirrhosis. Pediatr Int 43: 391–395.
Zhang A, Sun H, Han Y, Yan G, Wang X (2013) Urinary metabolic biomarker and pathway study of hepatitis B virus infected patients based on UPLC-MS system. PLoS One 8: e64381.
[26]
Ressom HW, Xiao JF, Tuli L, Varghese RS, Zhou B, et al. (2012) Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis. Anal Chim Acta 743: 90–100.
[27]
Byrd DJ, Wiltfang A, Rodeck B, Latta A, Burdelski M, et al. (1993) The plasma amino acid profile and its relationships to standard quantities of liver function in infants and children with extrahepatic biliary atresia and preterminal liver cirrhosis. Eur J Clin Chem Clin Biochem 31: 197–204.
[28]
Krahenbuhl S, Brass EP, Hoppel CL (2000) Decreased carnitine biosynthesis in rats with secondary biliary cirrhosis. Hepatology 31: 1217–1223.
[29]
Ramsay RR, Gandour RD, van der Leij FR (2001) Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 1546: 21–43.
[30]
Couce ML, Lopez-Suarez O, Boveda MD, Castineiras DE, Cocho JA, et al. (2013) Glutaric aciduria type I: outcome of patients with early- versus late-diagnosis. Eur J Paediatr Neurol 17: 383–389.
[31]
Fleming KE, Wanless IR (2013) Glutamine synthetase expression in activated hepatocyte progenitor cells and loss of hepatocellular expression in congestion and cirrhosis. Liver Int 33: 525–534.
[32]
Antoine DJ, Dear JW, Starkey-Lewis P, Platt V, Coyle J, et al. (2013) Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology. 58: 777–787.
[33]
Soga T, Sugimoto M, Honma M, Mori M, Igarashi K, et al. (2011) Serum metabolomics reveals gamma-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease. J Hepatol 55: 896–905.