Neonatal Intrahepatic Cholestasis Caused By Citrin Deficiency: Clinical Value Of Dynamic Alterations In Biochemical Markers

BackgroudNeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM #605814) is an autosomal recessive hereditary disease which was new discovered in recent years.This disease is one of the clinical phenotypes of citrin deficiency(CD). The earliest report on , NICCD was first publishdescribeded in 2001 by Ohura et al who revealed SLC25A13 gene mutations in Japanese infants with intrahepatic cholestasis with abnormalities at neonatal screening for inborn errors of metabolism and from then on this specific disorder entity was designate named as NICCD. In mainland of China, the first NICCD case with definite diagnosis was reported in 2006. The clinical presentations of NICCD usually occurs within the first several months of life, which werewere very difficult to be differentiated with from galactosemia, biliary obstruction, and other diseases like infantile hepatitis syndrome (IHS). However, the therapeutic measures and prognosis of the diseases above were quite different from each other, and the early diagnosis of NICCD was thus absolutely essential for its treatment and outcome improvement. Some NICCD patients passed away even at neonatal period due to severe hypoproteinemia and abnormal coaggulationliver dysfunction. Some others, several years or several decades later, developed into a new clinical phenotype clinical phenotype :Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) or another severe clinical phenotype adult-oneset type II citrullCTinemia (CTLN2, OMIM #603471)which presented as severe encephalopathy with liver transplantation as the unique reliable therapeutic choice. The development of CTLN2 from NICCD was maybe avoidable if the right diagnosis was made at earliery stage and dietary or medication therapy was given. At the current stage, the clinical or biochemical diagnostic criteria for NICCD remains to be established, and its definite diagnosis still relies on SLC25A13 analysis. Many research on NICCD have focused on the genetic diagnosis, however, studies on the biochemical indices still need to be accumulated. Actually, investigations on the features of dynamic changes in biochemical indices in NICCD cases and their differences from other diseases with similar clinical manifestations may provide valuable clues for the clinicial diagnosis of NICCD.ObjectiveThis study aims to explorestudy the dynamic change featurealteration of serum biochemical markers in NICCD patients, with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and to , simultaneously we compare them with biochemical markers withthose in other IHS patients without SLC25A13 mutation who have, so as to analyse its characteristics to facilitate the clinical differential diagnosis of NICCD, summarize its laws and characteristics, for an early diagnosis of NICCD.MethodsAll the subjects recruited in this study were totally 40 patients presenting with infantile hepatitis syndrome (HIS) (or cholestatic liver disease, CLD) infants, including 20 NICCD patientinfants whose diagnosis was diagnosedconfirmed by SLC25A13 genetic analysis were taken as NICCD group, while the remaining 20 cases without SLC25A13 mutations as havingnon- NICCD group. And two-stage groups dietary therapy protocol was performed on the NICCD subjects, with galactose-free formula at stage 1 and galactose-free and medium-chain triglyceride-enriched formula at stage 2 as the therapeutic feeds of treatments were done to patients with NICCD. Mainly use the HITACHI 7600 automatic biochemical analyzer to detect the serum levels of 22 serum biochemical markers in NICCD patient all subjects, who have different moon's age and treatments, inincluding transaminase, bilirubin, albumen, glucose and blood lipid were analyzed. We compare the biochemical markers of these NICCD patients before treatment, treatment stage 1 and stage 2, and at last compare the biochemical markers with other patients who have infant hepatitis syndrome..Results1. In NICCD patients, the serum levels of AST, S/L, ALP, GGT, TBIL, DBIL and TBA were rueduced in treatments, and while levels of TP and ALB elevated significantly in response to therapeutic formula intakeincreased.2. Compare to the non-NICCD patients, the infants with NICCD had significantly different bilchemical marker including ALT, S/L,ALP, LDH, GGT, TP, ALB, IBIL, TBA and Lact.3. This study revealed an every-pair is made and showed varied dependency relation. Positive correlation is found among the markers ALT, AST, TBIL and DBIL.And this correlation is also found among AST, ALP and GGT. TP and ALB were negatively correlationed with AFP.Conclusions1. The serum level of AST, S / L, ALP, GGT, TBIL, DBIL, TBA, TP, ALB changed regularly in the progress of NICCD, and they can be considered as complementaly diagnosis and prognosis assessment of NICCD. In NICCD cases, the serum level reduction in the biochemical markers including AST, DBIL, and TBA et al and the elevation in TP and ALB on therapeutic formula intake suggested the effectiveness of the two-stage dietary therapy.2. The findings in this study suggested that NICCD and non-NICCD subjects demonstrated quite different features of biochemical changes,which maybe helpful for their clinical differentiation.3. The biochemical markers of NICCD showed varied dependency relation between each other. Further investigationa are still needed to determine the cut-off points of the indices for the biochemical diagnosis of NICCD.