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Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry.

ABSTRACT: Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial NBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although their citrulline values exceeded the mean of the normal neonates and 80% of them surpassed +3 SD (standard deviation), all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in patients with NICCD compared to the control. By evaluating two indicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an estimated index comprising citrulline values and citrulline to total amino acid ratios could assure NICCD detection by NBS.

SUBMITTER: Shigetomi H

PROVIDER: S-EPMC7548893 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry.

Shigetomi Hiroko H Tanaka Toju T Nagao Masayoshi M Tsutsumi Hiroyuki H

International journal of neonatal screening 20180116 1

Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were ...[more]

PMID: 33072931

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Project description:BackgroundThe most common causes of cholestatic jaundice are biliary atresia and idiopathic neonatal hepatitis (INH). Specific disorders underlying INH, such as various infectious and metabolic causes, including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) especially, in East Asian populations are increasingly being identified. Since most NICCD infants recovered from liver disease by 1 year of age, they often are misdiagnosed with INH, leading to difficulty in determining the true prevalence of NICCD. Mutation(s) of human SLC25A13 gene encoding a mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), can lead to AGC2 deficiency, resulting in NICCD and an adult-onset fatal disease namely citrullinemia type II (CTLN2). To study the prevalence of NICCD and SLC25A13 mutations in Thai infants, and to compare manifestations of NICCD and non-NICCD, infants with idiopathic cholestatic jaundice or INH were enrolled. Clinical and biochemical data were reviewed. Urine organic acid and plasma amino acids profiles were analyzed. PCR-sequencing of all 18 exons of SLC25A13 and gap PCR for the mutations IVS16ins3kb and Ex16+74_IVS17-32del516 were performed. mRNA were analyzed in selected cases with possible splicing error.ResultsFive out of 39 (12.8%) unrelated infants enrolled in the study were found to have NICCD, of which three had homozygous 851del4 (GTATdel) and two compound heterozygous 851del4/IVS16ins3kb and 851del4/1638ins23, respectively. Two missense mutations (p.M1? and p.R605Q) of unknown functional significance were identified. At the initial presentation, NICCD patients had higher levels of alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) and lower level of alanine aminotransferase (ALT) than those in non-NICCD patients (p< 0.05). NICCD patients showed higher citrulline level and threonine/serine ratio than non-NICCD infants (p< 0.05). Fatty liver was found in 2 NICCD patients. Jaundice resolved in all NICCD and in 87.5% of non-NICCD infants at the median age of 9.5 and 4.0 months, respectively.ConclusionNICCD should be considered in infants with idiopathic cholestasis. The preliminary estimated prevalence of NICCD was calculated to be 1/48,228 with carrier rate of 1/110 among Thai infants. However, this number may be underestimated and required further analysis with mutation screening in larger control population to establish the true prevalence of NICCD and AGC2 deficiency.

Project description:BackgroundNeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) has high prevalence in East Asia, and has been reported in other parts of the world. NICCD is also the most common form of genetic cholestasis among East Asians. There has been reports of mortalities or liver transplants associated with NICCD, but risk factors associated with poor outcome were unknown. Our objective is to report NICCD mortalities in a tertiary pediatric hepatology center, and to explore associated risk factors along with implications to clinical practice.MethodThis is a retrospective analysis of NICCD cases collected from June 2003 until January 2017 in the Children's Hospital of Fudan University. Clinical, biochemical, and genetic data were compared between deceased cases and survivors without liver transplant.ResultsSixty-one confirmed NICCD cases, including 52 cases in the survival group, and 9 cases in the mortality group, were included in the analysis. Mean age at referral in the mortality group was significantly higher when compared to the survival group (9.58?±?5.03 VS 3.96?±?3.13?months, p?<?0.000). The proportion with infection in the mortality group was significantly higher than the survival group (p?=?0.023). 44.4% of patients in the mortality group did not receive lactose-free and/or medium chain triglycerides enriched (LF/MCT) formula, and this percentage was significantly higher than the survival group (9.6%, p?=?0.021). Mean platelet (PLT) count in the mortality group was significantly lower than the survival group (p?=?0.010). Mean serum gamma-glutamyl transpeptidase (GGT), and total cholesterol (TCH) levels were significantly lower in the mortality group when compared to the survival group with p values of 0.001, and 0.019, respectively. Those who died had higher serum ammonium levels than survivors (p?=?0.016). Mean level of citrulline was significantly lower in the mortality group compared to the survival group (p?=?0.010). On the other hand, mean level of tyrosine was significantly higher in the mortality group than that of the survival group (p?=?0.015).ConclusionLate referral, presence of infection, delayed treatment with LF/MCT formula, lower platelet count, lower levels of GGT, total cholesterol, blood citrulline, and higher level of blood ammonia and tyrosine, were associated with poor prognosis in NICCD.

Project description:To explore differences in biochemical indices between neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and that with other etiologies.Patients under 6 mo of age who were referred for investigation of conjugated hyperbilirubinaemia from June 2003 to December 2010 were eligible for this study. After excluding diseases affecting the extrahepatic biliary system, all patients were screened for the two most common SLC25A13 mutations; the coding exons of the entire SLC25A13 gene was sequenced and Western blotting of citrin protein performed in selected cases. Patients in whom homozygous or compound heterozygous SLC25A13 mutation and/or absence of normal citrin protein was detected were defined as having NICCD. Cases in which no specific etiological factor could be ascertained after a comprehensive conjugated hyperbilirubinaemia work-up were defined as idiopathic neonatal cholestasis (INC). Thirty-two NICCD patients, 250 INC patients, and 39 infants with cholangiography-confirmed biliary atresia (BA) were enrolled. Laboratory values at their first visit were abstracted from medical files and compared.Compared with BA and INC patients, the NICCD patients had significantly higher levels of total bile acid (TBA) [all measures are expressed as median (inter-quartile range): 178.0 (111.2-236.4) ?mol/L in NICCD vs 112.0 (84.9-153.9) ?mol/L in BA and 103.0 (70.9-135.3) ?mol/L in INC, P = 0.0001]. The NICCD patients had significantly lower direct bilirubin [D-Bil 59.6 (43.1-90.9) ?mol/L in NICCD vs 134.0 (115.9-151.2) ?mol/L in BA and 87.3 (63.0-123.6) ?mol/L in INC, P = 0.0001]; alanine aminotransferase [ALT 34.0 (23.0-55.0) U/L in NICCD vs 108.0 (62.0-199.0) U/L in BA and 84.5 (46.0-166.0) U/L in INC, P = 0.0001]; aspartate aminotransferase [AST 74.0 (53.5-150.0) U/L in NICCD vs 153.0 (115.0-239.0) U/L in BA and 130.5 (81.0-223.0) U/L in INC, P = 0.0006]; albumin [34.9 (30.7-38.2) g/L in NICCD vs 38.4 (36.3-42.2) g/L in BA and 39.9 (37.0-42.3) g/L in INC, P = 0.0001]; glucose [3.2 (2.0-4.4) mmol/L in NICCD vs 4.1 (3.4-5.1) mmol/L in BA and 4.0 (3.4-4.6) mmol/L in INC, P = 0.0014] and total cholesterol [TCH 3.33 (2.97-4.00) mmol/L in NICCD vs 4.57 (3.81-5.26) mmol/L in BA and 4.00 (3.24-4.74) mmol/L in INC, P = 0.0155] levels. The D-Bil to total bilirubin (T-Bil) ratio was significantly lower in NICCD patients [all measures are expressed as median (inter-quartile range): 0.54 (0.40-0.74)] than that in BA patients [0.77 (0.72-0.81), P = 0.001] and that in INC patients [0.74 (0.59-0.80), P = 0.0045]. A much higher AST/ALT ratio was found in NICCD patients [2.46 (1.95-3.63)] compared to BA patients [1.38 (0.94-1.97), P = 0.0001] and INC patients [1.48 (1.10-2.26), P = 0.0001]. NICCD patients had significantly higher TBA/D-Bil ratio [3.36 (1.98-4.43) vs 0.85 (0.72-1.09) in BA patients and 1.04 (0.92-1.14) in INC patients, P = 0.0001], and TBA/TCH ratio [60.7 (32.4-70.9) vs 24.7 (19.8-30.2) in BA patients and 24.2 (21.4-26.9) in INC patients, P = 0.0001] compared to the BA and INC groups.NICCD has significantly different biochemical indices from BA or INC. TBA excretion in NICCD appeared to be more severely disturbed than that of bilirubin and cholesterol.

Dataset Information

Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry.

Publications

Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry.

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