{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:47:22Z","timestamp":1792504042987,"version":"4.5.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a pan-ethnic complicated inborn error of metabolism but the specific mechanism is not fully understood.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A total of 169 patients with NICCD who have biallelic pathogenic <jats:italic>SLC25A13<\/jats:italic> variants detected by targeted next-generation sequencing were collected. They were divided into the \u201cNewborn-screen Group\u201d and \u201cClinical diagnosed Group\u201d depending on the newborn screening results. Amino acid and acylcarnitine profiles were measured by MS\/MS. The total bile acids, blood amino acids and acylcarnitines, general biochemistry, blood count, and coagulation parameters were monitored every 2\u20133\u00a0months. We compared the differences in metabolic indices and their dynamic changes between these two groups. The Mann\u2013Whitney test and orthogonal partial least squares discrimination analysis (OPLS-DA) were used for statistical analysis.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> At the onset of NICCD, we found that the \u201cClinical diagnosed Group\u201d had higher levels of intermediate products of the urea cycle, free carnitine, and short-chain and long-chain acylcarnitines than those in the \u201cNewborn-screen Group,\u201d but the levels of ketogenic\/glucogenic amino acids and several medium-chain acylcarnitines were lower. Furthermore, concentrations of direct bilirubin, total bile acid, lactate, prothrombin time, and several liver enzymes were significantly higher while total protein, amylase, and hemoglobin were lower in the \u201cClinical diagnosed Group\u201d than in the \u201cNewborn-screen Group.\u201d Dynamic change analysis showed that direct bilirubin, albumin, arginine, and citrulline were the earliest metabolic derangements to reach peak levels in NICCD groups, followed by acylcarnitine profiles, and finally with the elevation of liver enzymes. All abnormal characteristic metabolic indicators in the \u201cNewborn-screen Group\u201d came back to normal levels at earlier ages than the \u201cClinical diagnosed Group.\u201d c.852_855del (41.2%), IVS16ins3kb (17.6%), c.615 + 5G&amp;gt;A (9.6%), 1638_1660dup (4.4%), and c.1177 + 1G&amp;gt;A (3.7%) accounted for 76.5% of all the mutated <jats:italic>SLC25A13<\/jats:italic> alleles in our population.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Argininosuccinate synthesis, gluconeogenesis, ketogenesis, fatty acid oxidation, liver function, and cholestasis were more severely affected in the \u201cClinical diagnosed Group.\u201d The \u201cNewborn-screen Group\u201d had a better prognosis which highlighted the importance of newborn screening of NICCD.<\/jats:p>","DOI":"10.3389\/fmolb.2022.939837","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T09:53:00Z","timestamp":1661334780000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Dynamic changes of metabolic characteristics in neonatal intrahepatic cholestasis caused by citrin deficiency"],"prefix":"10.3389","volume":"9","author":[{"given":"Ting","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yezhen","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rulai","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benqing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12887-018-1383-5","article-title":"Risk factors associated with mortality in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and clinical implications","volume":"19","author":"Abuduxikuer","year":"2019","journal-title":"BMC Pediatr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ymgmr.2018.08.002","article-title":"Molecular and clinical characterization of citrin deficiency in a cohort of Chinese patients in Hong Kong","volume":"17","author":"Chong","year":"2018","journal-title":"Mol. 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