Neonatal Liver Disease Research Articles

Variable Clinical Spectrum of Inborn Errors of Bile Acid Synthesis: A Report of 10 Cases.

Inborn errors of bile acid synthesis are rare genetic disorders that usually present as neonatal cholestasis and liver disease in older children and adults. The symptomatology of inborn errors of bile acid synthesis can markedly vary among individuals, ranging from mild to severe conditions. Diagnosis is based on genetic tests and/or urine liquid secondary ionization mass spectrometry. Here, we have described characteristics of patients who were diagnosed with inborn errors of bile acid synthesis in our department. We retrospectively evaluated data from patients diagnosed with inborn errors of bile acid synthesis by urine bile acid analysis and/or genetic tests between 2013 and 2023. Ten patients (8 boys, 2 girls) born to consanguineous parents were diagnosed with inborn errors of bile acid synthesis during the study period. Six patients were diagnosed with 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, 2 patients with peroxisomal acyl-CoA oxidase 2 deficiency, and 2 patients with peroxisome biogenesis disorder. In patients with 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, 3 patients were monitored with cholic acid treatment, 2 underwent liver transplant due to liver failure, and 1 patient died from liver failure. Ursodeoxycholic acid treatment was given to patients with acyl-CoA oxidase 2 deficiency. Cholic acid was given to patients with peroxisome biogenesis disorder. Inborn errors of bile acid synthesis can cause a variety of liver diseases, from asymptomatic liver enzyme elevation to cirrhosis. Clinical findings may include neurological symptoms and fat and fat-soluble vitamin malabsorption complications. Deficiency of 3β-hydroxy-Δ5-C27-steroid dehydrogenase is the most common bile acid synthetic defect presenting in cholestasis in infancy and childhood. Cholic acid is effective for most patients with inborn errors of bile acid synthesis. If patients do not receive an early diagnosis, progressive liver disease or other serious complications may develop.

Fetal hemochromatosis: rare case of hepatic and extrahepatic siderosis involving thyroid on fetal MRI

BackgroundNeonatal hemochromatosis (NH) is a rare condition that is characterized by severe neonatal liver disease in association with hepatic and extrahepatic excess iron deposition (siderosis), while sparing the reticuloendothelial system. The most common cause of fetal liver injury leading to the NH phenotype (accounting for over 95% of cases) is gestational alloimmune liver disease. This condition is caused by the transfer of maternal IgG antibodies through the placenta, targeting a fetal hepatocyte antigen. Prenatal diagnosis, particularly the identification of iron overload involving both liver and thyroid, is of significant importance and can have a profound impact on patient care. To our knowledge, no case has been reported on prenatal diagnosis of iron overload involving both liver and thyroid.Case presentationWe present an exceptionally rare case of fetal hemochromatosis in a primigravida, a case that significantly contributes to our understanding of this condition. The diagnosis was made with the presence of hepatic and extrahepatic siderosis involving the thyroid using Ultrasonography (USG) and fetal Magnetic Resonance Imaging (MRI) findings. A 23-year-old primigravida was referred to our center in view of oligohydramnios, Intrauterine Growth Restriction (IUGR) and echogenic bowel at 29 weeks of gestation. USG and fetal MRI showed features of coarse liver echotexture and iron overload involving the liver and thyroid; this is the first case describing iron accumulation in the fetal thyroid gland diagnosed in utero.ConclusionThis case underscores the critical importance of performing MRI in suspected cases of fetal hemochromatosis for early diagnosis and intervention, emphasizing the potential to significantly improve patient outcomes.

Kinesin family member 12-related hepatopathy: A generally indolent disorder with elevated gamma-glutamyl-transferase activity.

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma-glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12-related disease from other entities with elevated GGT.

Neurometabolic changes in a rat pup model of type C hepatic encephalopathy depend on age at liver disease onset

Chronic liver disease (CLD) is a serious condition where various toxins present in the blood affect the brain leading to type C hepatic encephalopathy (HE). Both adults and children are impacted, while children may display unique vulnerabilities depending on the affected window of brain development.We aimed to use the advantages of high field proton Magnetic Resonance Spectroscopy (1H MRS) to study longitudinally the neurometabolic and behavioural effects of Bile Duct Ligation (animal model of CLD-induced type C HE) on rats at post-natal day 15 (p15) to get closer to neonatal onset liver disease. Furthermore, we compared two sets of animals (p15 and p21-previously published) to evaluate whether the brain responds differently to CLD according to age onset.We showed for the first time that when CLD was acquired at p15, the rats presented the typical signs of CLD, i.e. rise in plasma bilirubin and ammonium, and developed the characteristic brain metabolic changes associated with type C HE (e.g. glutamine increase and osmolytes decrease). When compared to rats that acquired CLD at p21, p15 rats did not show any significant difference in plasma biochemistry, but displayed a delayed increase in brain glutamine and decrease in total-choline. The changes in neurotransmitters were milder than in p21 rats. Moreover, p15 rats showed an earlier increase in brain lactate and a different antioxidant response. These findings offer tentative pointers as to which neurodevelopmental processes may be impacted and raise the question of whether similar changes might exist in humans but are missed owing to 1H MRS methodological limitations in field strength of clinical magnet.

Lipid strategies to prevent intestinal failure-associated liver disease in neonates: A pilot trial.

Intestinal failure-associated liver disease (IFALD) occurs in up to 50% of neonates treated with prolonged parenteral nutrition. Preventative strategies for IFALD include soybean oil lipid emulsion (SOLE) minimization and use of mixed-oil intravenous lipid emulsions (ILE). We conducted a pilot study prospectively comparing these two ILE strategies in the prevention of IFALD in neonates who required abdominal surgery. We randomized eligible neonates to SOLE at 1 g/kg/day (SOLE Min) or mixed-oil ILE containing fish oil (MOLE) at 3 g/kg/day. These treatment groups were also compared with historic controls who received SOLE at 2-3 g/kg/day (SOLE Historic). We defined IFALD as a direct bilirubin >2 mg/dl on two measurements. Secondary outcomes included laboratory, growth, clinical, and nutrition outcomes. A total of 24 prospective and 24 historic patients were included. There was no difference in the rate of IFALD. However, there was a difference in the weekly change of direct bilirubin levels (SOLE Historic +0.293 mg/dl/week vs MOLE, P < 0.001; SOLE Min +0.242 mg/dl/week vs MOLE, P < 0.001). The MOLE group also had a lower direct bilirubin at study completion (SOLE Historic, 1.7 ± 1.7 mg/dl; SOLE Min, 1.6 ± 1.4 mg/dl; MOLE, 0.4 ± 0.4 mg/dl; P = 0.002) and received greater total calories (P = 0.008). The rate of IFALD did not differ when comparing ILE strategies in neonates requiring abdominal surgery. However, the MOLE group maintained significantly lower direct bilirubin levels over time while receiving increased calories. This pilot study highlights the need for further randomized controlled trials comparing these ILE strategies.

Association between congenital heart disease and parenteral nutrition-associated liver disease in neonates: A retrospective cohort study.

Infants receiving parenteral nutrition (PN) are at increased risk of PN-associated liver disease (PNALD), which can lead to hepatic fibrosis. Congenital heart disease (CHD) represents a risk factor for hepatic fibrosis, so this study sought to better understand whether infants with CHD were at elevated risk of PNALD when receiving long-term PN. This study includes a retrospective cohort of infants at a level IV neonatal intensive care unit from 2010 to 2020 who received long-term PN during the first 8 weeks of life. A time-varying Cox survival model was used to model risk of PNALD between infants with and without CHD, adjusted for demographics, surgical intervention, and PN exposure, using a 5000-iteration bootstrap estimation. Secondary analyses evaluated risk against discrete CHD diagnoses, and sensitivity analysis was performed on the magnitude and quantity of direct bilirubin laboratory measurements making up the PNALD definition. Neonates with CHD were found to be at higher risk for PNALD during or soon after long-term PN exposure. A pattern of increasing association strength with increasing bilirubin threshold suggests infants with CHD may also experience higher degrees of injury. This work offers a step in understanding how diagnoses can be factored into neonate PN prescription. Future work will explore modifications in lipid profiles and timing to mitigate risk in patients with CHD.

Metabolic regulation of cholestatic liver injury by D-2-hydroxyglutarate with the modulation of hepatic microenvironment and the mammalian target of rapamycin signaling

Biliary atresia (BA) is a cholestatic liver disease in neonates with devastating obstructive intrahepatic and extrahepatic biliary ducts. Owing to the lack of an early diagnostic marker and limited understanding of its pathogenesis, BA often leads to death within 2 years. Therefore, this study aimed to develop early diagnostic methods and investigate the underlying pathogenesis of liver injury in BA using metabolomics. Metabolomics and organoid combined energy metabolism analysis was used to obtain new insights into BA diagnosis and pathobiology using patient samples, mice liver organoids, and a zebrafish model. Metabolomics revealed that D-2-hydroxyglutarate (D-2-HG) levels were significantly elevated in the plasma and liver of patients with BA and closely correlated with liver injuries and impaired liver regeneration. D-2-HG suppressed the growth and expansion of liver organoids derived from the intrahepatic biliary ducts. The energy metabolism analysis demonstrated that D-2-HG inhibited mitochondrial respiration and ATP synthase; however, it increased aerobic glycolysis in organoids. In addition, D-2-HG exposure caused liver degeneration in zebrafish larvae. Mechanistically, D-2-HG inhibited the activation of protein kinase B and the mammalian target of rapamycin signaling. These findings reveal that D-2-HG may represent a novel noninvasive diagnostic biomarker and a potential therapeutic target for infants with BA.

Neonatal Lupus presenting with neonatal hemochromatosis-like liver disease that responded to steroids: a case report

BackgroundNeonatal lupus erythematosus is a rare multisystem autoimmune disorder that predominantly involves the heart with congenital heart block but can involve other organs including the liver. The disease results from passage of maternal autoantibodies to the fetus and manifests in various forms depending on the organ involved. Neonatal lupus liver disease manifestations range from benign elevation in aminotransferases to fatal hepatic insufficiency with iron deposition that does not respond to therapy. Only a handful of cases have been reported to date. The antibodies implicated are Sjogren Syndrome types A and B antibodies. Other non-specific autoantibodies can be positive as well such as antinuclear antibodies. Smooth muscle antibodies are classically considered specific to autoimmune hepatitis, and while they have been described in other chronic liver diseases, they have not been described in neonatal lupus liver disease. Herein we report a rare case of neonatal cholestasis due to neonatal lupus liver disease that presented with a positive smooth muscle antibodies in addition to a biochemical picture of neonatal hemochromatosis, with a remarkably elevated ferritin, that responded well to steroid therapy. Case presentationAn 8-day old full-term baby girl was referred to our center for evaluation of neonatal bradycardia and generalized jaundice that started in the first day of life. Prenatal history was significant for fetal bradycardia. Examination was unremarkable except for bradycardia and generalized jaundice. Laboratory findings included elevated alanine aminotransferase, aspartate aminotransferase, Alkaline Phosphatase, and total and direct bilirubin. Her ferritin was markedly elevated along with triglycerides. Sjogren syndrome antibodies were positive in addition to antinuclear and anti-smooth muscle antibodies. The diagnosis of cardiac neonatal lupus was given, and her liver disease was attributed to lupus despite the biochemical picture of neonatal hemochromatosis. She was started on oral prednisolone for which her liver function parameters showed a dramatic response and continued to be within the normal limits several weeks after discontinuation of steroids.ConclusionNeonatal lupus liver disease is a rare cause of neonatal cholestasis that can rarely present with neonatal hemochromatosis picture which unlike other causes of neonatal hemochromatosis can be reversed with steroid therapy.

Comprehensive Analysis of Gut Microbiota and Fecal Bile Acid Profiles in Children With Biliary Atresia.

BackgroundBiliary atresia (BA) is the most common cholestatic liver disease in neonates. Herein, we aimed at characterizing the gut microbiota and fecal bile acid profiles of BA patients, defining the correlations between them, and evaluating the relationship between the clinical pathogenesis and changes in the gut microbiota and bile acid profiles.MethodsA total of 84 fecal samples from BA patients (n = 46) and matched healthy controls (HCs, n = 38) were subjected to sequencing by 16S rRNA gene amplification, and fecal bile acid were analyzed by targeted metabolomics.FindingsCompared with the controls, a structural separation of the intestinal flora of BA patients was uncovered, which was accompanied by changes in the composition of fecal bile acids. In the BA group, Actinobacillus, Monoglobus, and Agathobacter were enriched in patients without cholangitis (p < 0.05). Selenomonadaceae and Megamonas were more abundant in patients without recurrent cholangitis episodes (p < 0.05), while Lachnospiraceae and Ruminococcaceae were enriched in patients with multiple recurrences of cholangitis (p < 0.05). Postoperative jaundice clearance was associated with Campylobacter and Rikenellaceae (p < 0.05), and tauroursodeoxycholic acid was associated with jaundice clearance (p < 0.001).ConclusionBA patients are characterized by different compositions of gut microbiota and bile acids, and their interaction is involved in the process of liver damage in BA, which may be closely related to the occurrence of postoperative cholangitis and jaundice clearance.

Elevated Alpha-Fetoprotein in Infantile-Onset Niemann-Pick Type C Disease with Liver Involvement.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive neuro-visceral lipid storage disease. We describe nine cases of infantile-onset NPC with various genetic mutations in the NPC1 gene, which presented with neonatal cholestasis. Serum alpha-fetoprotein (AFP) levels were obtained as part of their workup during the first four months of life. In eight of nine (89%) patients, serum AFP demonstrated elevated levels. Seven infants displayed marked elevations, ranging from 4 to 300 times the upper limit for age-adjusted norms. In most patients, AFP levels peaked during the initial test and declined over time as cholestasis resolved. We conclude that elevated AFP levels are a common, although non-specific, marker for NPC-associated liver disease. These findings demonstrate the benefit of including AFP levels in the workup of neonatal liver disease, especially if there is accompanied cholestasis and if NPC is suspected.

Role of long non-coding RNA-adducin 3 antisense RNA1 in liver fibrosis of biliary atresia

ABSTRACT Biliary atresia (BA) is a devastating liver disease in neonates. Liver fibrosis is regarded as a universal and prominent feature of BA. Studies have revealed that long non-coding RNAs (lncRNAs) regulate cellular processes during the development of liver fibrosis in BA. Long non-coding RNA-adducin 3 antisense RNA1 (lnc-ADD3-AS1) has been shown to increase susceptibility to BA. However, the role of lnc-ADD3-AS1 in liver fibrosis in BA remains unclear. Here, we investigated the role of lnc-ADD3-AS1 in the proliferation, migration, and apoptosis of the immortalized human hepatic stellate cell (HSC) line, LX-2. We successfully overexpressed and silenced lnc-ADD3-AS1 in LX-2 cells using adenovirus vectors and evaluated the proliferation of transfected cells using the Cell Counting Kit-8 (CCK8) assay. Cell apoptosis was detected using annexin V–fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining and flow cytometry. We then analyzed cell migration by performing wound-scratch and transwell migration assays. Our results show that lnc-ADD3-AS1 significantly promoted LX-2 cell proliferation and attenuated apoptosis. More importantly, lncRNA-ADD3-AS1 significantly accelerated the migration of LX-2 cells. Our data indicated that lncRNA-ADD3-AS1 plays a role in the pathogenesis of liver fibrosis in patients with BA and may serve as a potential diagnostic marker for monitoring liver fibrosis in BA or as a therapeutic target for the disease.

Could distal variants in ALG13 lead to atypical clinical presentation?

Congenital disorders of glycosylation (CDG) represent a wide range of some 150 inherited metabolic diseases, continually expanding in terms of newly identified genes and the heterogeneity of clinical and molecular presentations within each subtype. Heterozygous pathogenic variants in ALG13 are associated with early-onset epileptic encephalopathy, typically in females. The majority of subjects described so far harbour one of the two recurrent pathogenic variants, namely p.(Asn107Ser) and p.(Ala81Thr) in the C-terminal glycosyltransferase domain. We report a novel ALG13 variant (c.1709G > A, p.(Gly570Glu)) in an adult female with unremarkable past developmental and medical history, except for mild kinetic tremor. Our proband presented with acute onset of neurological and psychiatric features, along with liver dysfunction, during pregnancy, all of which gradually resolved after delivery. The proband's newborn baby died at 22 days of life from neonatal liver disease, due to gestational alloimmune liver disease (GALD). Functional assessment on fibroblasts derived from our case showed alterations in 2 of 3 cellular glycosylation markers (LAMP2, Factor IX), suggesting a functional effect of this novel ALG13 variant on glycosylation. This paper raises the possibility that variants outside the glycosyltransferase domain may have a hypomorphic effect leading to atypical clinical manifestations.

Protocol for a diagnostic accuracy study to develop diagnosis algorithm for biliary atresia using MMP-7 (DIABA-7 study): a study recruiting from Chinese Biliary Atresia Collaborative Network

IntroductionBiliary atresia is a severe liver disease in neonates, and the prognosis partially depends on the age at which infants undergo the Kasai procedure. Matrix metalloproteinase-7 (MMP-7) was confirmed to...

Newborn Screening for Biliary Atresia: a Review of Current Methods

Biliary atresia is a serious neonatal liver disease due to obstructed bile ducts that has better outcomes when detected and treated in the first 30-45days of life. This review examines different methods to screen newborns for biliary atresia as well as discusses observations from ongoing screening programs implemented in parts of the United States. Screening strategies for biliary atresia include detecting persistent jaundice, examining stool color, testing fractionated bilirubin levels, or measuring bile acid levels from dried blood spot cards. The stool color card program is the most widely used screening strategy worldwide. An alternative approach under investigation in the United States measures fractionated bilirubin levels, which are abnormal in newborns with biliary atresia. Fractionated bilirubin screening programs require laboratories to derive reference ranges, nurseries to implement universal testing, and healthcare systems to develop infrastructure that identifies and acts upon abnormal results. Biliary atresia meets the disease-specific criteria for newborn screening. Current studies focus on developing a strategy which also meets all test-specific criteria. Such a strategy, if implemented uniformly, has the potential to accelerate treatment and reduce biliary atresia's large liver transplant burden.

Effects of Previous Kasai Surgery on Gut Microbiota and Bile Acid in Biliary Atresia With End-Stage Liver Disease.

Background and Aims: Biliary atresia (BA) is the most common cholestatic liver disease in neonates. Although the Kasai procedure can improve temporary biliary drainage in some cases, complications and liver fibrosis still develop. Liver transplantation is the ultimate treatment. The current study aimed to investigate the effect of previous Kasai surgery on gut microbiota and bile acid in BA with end-stage liver disease.Methods: Patients with BA with end-stage liver disease were divided into two groups according to whether they had previously undergone Kasai surgery (non-Kasai: n = 8, post-Kasai: n = 8). Metagenomic sequencing and ultraperformance liquid chromatography/tandem mass spectrometry were performed to identify the gut microbiota and bile acid.Results: Previous Kasai surgery had some effects on gut microbiota and bile acid in BA with end-stage liver disease. In the gut microbiome, the differential species were mainly distributed at the species level. Veillonella atypica had a significant increase in the non-Kasai group (P < 0.05). Bacteroides spp., Prevotella spp., Barnesiella spp., Parabacteroides spp., Heliobacterium spp., Erysipelatoclostridium spp. and Diaporthe spp. were increased in the post-Kasai group (P < 0.05). Concerning functional profiles, methionine biosynthesis was enriched in the non-Kasai group, while pyridoxal biosynthesis and riboflavin biosynthesis were enriched in the post-Kasai group (linear discriminant analysis > 2, P < 0.05). In stools, 17 bile acids were distinctly elevated in the post-Kasai group, such as cholic acid, chenodeoxycholic acid, β-muricholic acid and tauro α-muricholate (P < 0.05). Spearman correlation test showed that V. atypica had an enormously positive correlation with liver enzymes. Faecalibacterium prausnitzii and Escherichia coli were associated with derivatives of the alternative pathway of bile acid metabolism.Conclusion: Previous Kasai surgery can improve the gut microbiota and bile acid in patients with BA with end-stage liver disease. This improvement contributes to maintaining the intestinal barrier.

Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia.

In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was to investigate whether serological detection of caspase activation mirrors apoptotic liver injury in the infective murine BA-model and represents a suitable biomarker for BA in humans. Analysis showed increased caspase-3 activity and apoptosis in the livers of cholestatic BALB/c mice, which correlated significantly with caspase activation in the serum. We then investigated caspase activation and apoptosis in liver tissues and sera from 26 BA patients, 23 age-matched healthy and 11 cholestatic newborns, due to other hepatopathies. Compared to healthy individuals, increased caspase activation in the liver samples of BA patients was present. Moreover, caspase-3 activity was significantly higher in sera from BA infants compared to patients with other cholestatic diseases (sensitivity 85%, specificity 91%). In conclusion, caspase activation and hepatocyte apoptosis play an important role in experimental and human BA. We demonstrated that serological detection of caspase activation represents a reliable non-invasive biomarker for monitoring disease activity in neonatal cholestatic liver diseases including BA.

Preventive effect of prophylactic intravenous antibiotics against cholangitis in biliary atresia: a randomized controlled trial.

Biliary atresia (BA) is a neonatal liver disease and requires Kasai portoenterostomy. Many patients develop postoperative cholangitis, resulting in a poor prognosis. The preventive strategy of antibiotics is empirical and lacks a standard regimen. We aimed to analyze the effect of different durations of prophylactic intravenous antibiotics against post-Kasai cholangitis. A single-center, open-labeled, randomized clinical trial was performed from June 2016 to August 2017. One hundred and eighty BA patients were recruited and randomized into a short-term (n = 90) and a long-term (n = 90) treatment group, and prophylactic intravenous antibiotics were used for 7 versus 14days, respectively. The primary outcome was the overall cholangitis incidence within 6-months post-Kasai portoenterostomy. The secondary outcomes included cholangitis incidence within 1 and 3months post-Kasai portoenterostomy, the onset and average episodes of cholangitis, jaundice clearance rate, native liver survival rate, and adverse events within 6-months post-Kasai portoenterostomy. The cholangitis incidence within 6-months post-Kasai in the short-term group was similar to the long-term group (62% vs. 70%, p = 0.27) with intention-to-treat and pre-protocol analysis. There was no significant difference in jaundice clearance rate or native liver survival rate between the two groups. However, the percentage of early onset (61% vs. 38%, p = 0.02) and average episodes (2.4 ± 0.2 vs. 1.8 ± 0.1 episodes, p = 0.01) of cholangitis were lower in the long-term group. Long-term intravenous antibiotics can be replaced by the short-term regimen in the general protection against post-Kasai cholangitis.

Development and Assessment of Screening Nomogram for Biliary Atresia Based on Hepatobiliary Ultrasonographic Features.

Objectives: Biliary atresia (BA) is a rare neonatal liver disease of which the early diagnosis remains a challenge for clinicians. Our center has established a nomogram diagnostic model based on clinical characteristics and liver function characteristics. We aim to develop and validate a nomogram that includes additional ultrasound and finds hepatobiliary abnormality with better BA early screening performance.Methods: In this single-center, retrospective cohort analysis, 1,001 neonatal obstructive jaundice (NOJ) patients between 2012 and 2015 were enrolled. Multivariable analysis was used to identify clinical characteristics, laboratory liver function characteristics, and ultrasonic features that may early screen BA. A nomogram was developed to predict the probability of BA using multiple logistic regression analysis. This nomogram was subsequently validated using another cohort of 501 NOJ patients between 2015 and 2017. Calibration curve analysis and decision curve analyses were performed to evaluate and interpret the nomogram's clinical benefits.Results: Gender, direct bilirubin (DB), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), fasting gallbladder visibility, fasting gallbladder filling, and common bile duct visibility were found to have profound statistical significance between the BA and non-BA groups (P < 0.05). The significant features were used to build the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) value of the novel nomogram (0.87) was superior to those of the former nomogram (0.83) and GGT alone (0.81) in the prediction of BA. The calibration curve revealed a close resemblance between the predicted and actual BA probabilities. Also, the net benefit from the decision curve analysis (DCA) of the nomogram (0.54) was superior to those of the former nomogram (0.49) and GGT alone (0.45) at 80% of threshold possibility.Conclusions: The nomogram has demonstrated better performance for BA screening by including additional information of the US finding, holding a promising future as a non-invasive method for BA patients.

Impact of Parenteral Lipid Emulsion Components on Cholestatic Liver Disease in Neonates

Total parenteral nutrition (TPN) is a life-saving intervention for infants that are unable to feed by mouth. Infants that remain on TPN for extended periods of time are at risk for the development of liver injury in the form of parenteral nutrition associated cholestasis (PNAC). Current research suggests the lipid component of TPN is a factor in the development of PNAC. Most notably, the fatty acid composition, vitamin E concentration, and presence of phytosterols are believed key mediators of lipid emulsion driven PNAC development. New emulsions comprised of fish oil and medium chain triglycerides show promise for reducing the incidence of PNAC in infants. In this review we will cover the current clinical studies on the benefit of fish oil and medium chain triglyceride containing lipid emulsions on the development of PNAC, the current constituents of lipid emulsions that may modulate the prevalence of PNAC, and potential new supplements to TPN to further reduce the incidence of PNAC.

Adenosine kinase deficiency: Three new cases and diagnostic value of hypermethioninemia

Adenosine kinase (ADK) deficiency is characterized by liver disease, dysmorphic features, epilepsy and developmental delay. This defect disrupts the adenosine/AMP futile cycle and interferes with the upstream methionine cycle. We report the clinical, histological and biochemical courses of three ADK children carrying two new mutations and presenting with neonatal cholestasis and neurological disorders. One of them died of liver failure whereas the other two recovered from their liver damage. As the phenotype was consistent with a mitochondrial disorder, we studied liver mitochondrial respiratory chain activities in two patients and revealed a combined defect of several complexes. In addition, we retrospectively analyzed methionine plasma concentration, a hallmark of ADK deficiency, in a cohort of children and showed that methionine level in patients with ADK deficiency was strongly increased compared with patients with other liver diseases. ADK deficiency is a cause of neonatal or early infantile liver disease that may mimic primary mitochondrial disorders. In this context, an elevation of methionine plasma levels over twice the upper limit should not be considered as a nonspecific finding. ADK deficiency induced-liver dysfunction is most often transient, but could be life-threatening.