Comparative Study Of Sodium Taurocholate Cotransporting Polypeptide Deficiency And Neonatal Intrahepatic Cholestasis Caused By Citrin Deficiency

Aims Deficiency of sodium taurocholate cotransporting polypeptide(NTCP)is an inborn error of bile acid metabolism caused by biallelic SLC10A1 variants,but the patient number of this disease was still reported rather limitedly and its clinical features remain far from being completely understood.Neonatal intrahepatic cholestasis caused by citrin deficiency(NICCD)is an autosomal recessive disease caused by biallelic variants of SLC25A13 gene which encodes citrin protein.Both NTCP deficiency and NICCD may manifest as cholestasis in early infancy,but their therapeutics and prognosis are completely different.This study aimed to explore the differences in the clinical manifestations,laboratory findings and metabolome changes between the patients with NTCP Deficiency and NICCD,so as to provide evidence for their differential diagnosis.Methods The research subjects in this study were divided into two groups: 14 patients with NTCP deficiency and 18 ones with NICCD,who were diagnosed and treated in the Department of Pediatrics,the First Affiliated Hospital,Jinan University.The clinical manifestations,blood routine indices,biochemistry alterations and metabolome changes were collected and analyzed.The comparison of the rate of nonquantitative data was carried out with Fisher’s test.Quantitative data with normal distribution were presented as mean ± standard deviation((?)±s),and compared by using Student’s t test,the data with heterogeneity of variance were compared by separate variance estimation t-test.Besides,the data with non-normal distribution were described with medians(interquartile range),and compared by Wilcoxon rank sum test,with P<0.05 as the significance criteria.Results(1)Patients suffering from NTCP deficiency or NICCD may undergo cholestasis,but the incidence of cholestasis(100% vs 21.4%,P=0.000)and hepatomegaly(94.4% vs 0%,P=0.000)in NICCD group are higher than those in NTCP deficiency group.(2)Compared with NTCP deficiency,NICCD group had the lower levels of hemoglobin(106.61±14.27 vs 129.89±23.23,t=3.233,P=0.003)and mean corpuscular hemoglobin(28.90±2.75 vs 31.82±2.53,t=2.107,P=0.049)at early stage.(3)Compared with NICCD,NTCP deficiency group had the higher levels of serum total bilirubin [205.20(169.15,237.65)vs 150.50(127.08,178.68),Z=4.505,P=0.000] and Indirect bilirubin [175.60(138.51,222.15)vs 67.70(60.60,107.50),Z=3.133,P=0.002],as well as the lower levels of serum total bile acids(111.56±34.85 vs 241.68±83.35,t=5.515,P=0.000),direct bilirubin[17.17(13.15,20.10)vs 70.10(42.50,86.60),Z=4.558,P=0.000],DBIL/TBIL ratio [0.09(0.07,0.17)vs 0.48(0.36,0.58),Z=4.505,P=0.025],alkaline phosphatase [324.00(173.75,487.50)vs 1017.53(703.33,1141.70),Z=3.900,P=0.004],alanine aminotransferase [22.00(12.35,40.80)vs 48.20(36.00,54.00),Z=2.002,P=0.004],aspartate aminotransferase [43.50(33.00,52.18)vs 112.50(86.50,152.03),Z=3.725,P=0.000],compared with NTCP deficiency,NICCD group had the lower levels of total protein(45.91±7.22 vs 54.98±5.53,t=3.621,P=0.001)and albumin(31.52±6.20 vs 39.02±3.85,t=3.679,P=0.001),.(4)Compared with NTCP deficiency,NICCD group had higher levels of serum magnesium(1.00±0.12 vs 0.86±0.08,t=3.882,P=0.001),iron(18.42±5.60 vs 12.94±4.40,t=2.927,P=0.007)and ceruloplasmin [0.38(0.25,0.43)vs 0.24(0.19,0.27),Z=2.416,P=0.016].(5)Compared with NTCP deficiency,NICCD group had higher rates of elevated citrulline(100% vs 0%,P=0.003)and methionine(100% vs 33.3%,P=0.033)in blood and 4-hydroxyphenyllactate in urine(100% vs 0%,P=0.003).Conclusions(1)Compared with NTCP deficiency,NICCD had the higher incidence of cholestasis,and hepatomegaly is the important evidence for the differentiation of NTCP deficiency and NICCD.(2)At the early stage,the lower levels of hemoglobin and Mean content of hemoglobin in NICCD will be valuable for the differentiation of NTCP deficiency and NICCD.(3)Compared with NTCP deficiency,NICCD had the lower levels of serum total protein and albumin,and the higher levels of serum total bile acid,direct bilirubin,DBIL/TBIL ratio,alkaline phosphatase,ALT and AST at the early stage.Compared with NICCD,NTCP deficiency had the higher levels of serum total bilirubin and indirect bilirubin at their first visit.(4)On metabolome analysis,the raised levels of citrulline and methionine in blood and 4-hydroxyphenyllactate in urine could facilitate the differentiation of NICCD from NTCP deficiency.