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Aim of the study: Biliary atresia (BA) is an important cause of surgical jaundice. Although the precise etiology is unknown, ß-amyloid (Aß) has been observed around the bile ducts in BA livers. It is unclear whether Aß plays a role in the pathogenesis of this disease. This study aims to assess the amyloid ß precursor protein (APP) gene expression in infants with BA in comparison with other causes of neonatal cholestasis. This could help explore the role of Aß in the pathogenesis and diagnosis of BA. Material and methods: A prospective study was conducted at the outpatient clinic of Paediatric Hepatology, Gastroenterology, and Nutrition Department, National Liver Institute, Menoufia University, Shebin El Kom, Menoufia, Egypt during the period March 2022 to December 2022. Clinical data were gathered and laboratory and radiological investigations were conducted including ß precursor protein gene expression measured in liver biopsies of the three groups using quantitative real-time PCR (qPCR). Results: Gene expression of APP was considerably higher in the BA group (p = 0.0001) compared to neonatal cholestasis (NC) patients. Gamma glutamyl transferase (GGT) and APP had a positive correlation (p = 0.001). No significant association was found between APP and fibrosis. APP was noticeably higher in BA than NC other than BA. Also, APP in BA was higher (statistically significant, p = 0.0001) than the control. There was no statistically significant difference among NC, BA, and control groups regarding APP (p = 0.07). Both males and females did not show significant differences as regards APP (p = 0.851). Age did not have a statistically significant correlation with APP (p = 0.532). Also, there were no correlations between APP and alkaline phosphatase (ALP), aspartate transaminase (AST), or total bilirubin (TB) (p > 0.05). Conclusions: We concluded that the development and identification of BA may depend on the liver expression of serum APP. Surgeons may be able to carry out early intraoperative cholangiography for BA confirmation if the combination of APP with GGT and other hepatic function parameters exhibits a high predictive potential as a diagnostic test for BA. To evaluate this hypothesis, more research with sizable sample numbers is necessary. [ABSTRACT FROM AUTHOR]

Objective: This study aims to detect a relationship between inflammatory markers, ductus venosus (DV) pulsatility index (PI), middle cerebral artery (MCA) PI, and umbilical artery (UA) systole to diastole ratio (S/D) and PI between pregnancies with intrahepatic cholestasis and control cases. Methods: This prospective study included 82 cases having intrahepatic cholestasis of pregnancy (ICP) and 80 gestational age-matched healthy control cases. The Doppler measurements (DV PI, MCA PI, and UA S/D and PI), inflammatory markers (neutrophil to lymphocyte ratio [NLR], platelet to lymphocyte ratio [PLR], mean platelet volume [MPV], and red blood cell distribution width [RDW]), and fetal and maternal outcomes were compared. Results: Patients with ICP had increased PLR value (p=0.019) and decreased lymphocyte count (p=0.004) compared to control cases. Also, there was a positive correlation between PLR value and the presence of ICP (Χ²=5.774, p=0.016). There were no significant differences between ICP and control groups concerning NLR, RDW, MPV, and UA PI values. We found higher UA S/D, and DV PI values and lower MCA PI values in pregnancies with ICP compared to controls (p<0.001, p=0.026, and p=0.003, respectively). Conclusion: In ICP cases, the PLR value was significantly increased than the controls, but the NLR, RDW, MPV, and UA PI values were found to be similar to control cases. The UA S/D, and DV PI values were increased, and MCA PI was significantly decreased in the ICP group compared to healthy pregnancies. However, we could not demonstrate the benefit of Doppler measurements in predicting neonatal outcomes in ICP cases. [ABSTRACT FROM AUTHOR]

Background and Objective: Niemann-Pick type C is a rare lysosomal storage disorder causing cholesterol intracellular transport deficiency. Typically found in children, it causes neurological deterioration and age-related symptoms. In this article, two cases of Niemann-Pick type C1 with cholestasis and another case with a compound heterozygous mutation that included Niemann-Pick type D are presented. Although neonatal diseases are the most common cause of early cholestasis, this report emphasizes the importance of considering storage disease in cholestasis. Case Report: A 34-day-old female baby born to a third-degree married couple at 38 weeks gestation presented with cholestatic jaundice. Whole-exome sequencing suggested an NPC1 gene mutation and Niemann-Pick type C. A 35-day-old female baby born at 39 weeks gestation presented with ecchymotic patches, decreased feed acceptance, greenish discoloration of the eyes, high-color urine, and firm hepatosplenomegaly. The child was worked up for conjugated hyperbilirubinemia and a liver biopsy in favor of Niemann-Pick disease. Whole exome sequencing showed an NPC1 gene heterozygous mutation, suggesting Niemann-Pick disease types C and D. Conclusion: Pediatricians should consider Niemann-Pick disease in neonates with persistent cholestasis. [ABSTRACT FROM AUTHOR]

Background: Intestinal failure–associated liver disease (IFALD), initially manifesting as cholestasis, is a complication in neonates receiving parenteral nutrition (PN). Soybean oil lipid emulsion (SOLE), though implicated in IFALD, was the only US Food and Drug Administration (FDA)–approved initial intravenous lipid emulsion (ILE) for infants and children in the United States. A mixed‐oil lipid emulsion (MOLE) gained popularity in patients at risk for IFALD and was recently FDA approved as an initial ILE in children. Given the presence of soybean oil in MOLE, we hypothesized that MOLE would not be effective at preventing cholestasis in surgical neonates. Methods: Neonates with gastrointestinal surgical conditions necessitating PN for ≥14 days and receiving MOLE (SMOFlipid) from July 2016 to July 2019 were analyzed retrospectively. Unpaired and pair‐matched historical surgical neonates treated with SOLE (Intralipid) served as controls. The primary outcome measure was development of cholestasis (direct bilirubin ≥2 mg/dl). Results: Overall, 63% (10 of 16) of MOLE patients and 22% (30 of 136) of SOLE patients developed cholestasis after ≥14 days of therapy (P = 0.005). The latency to developing cholestasis was significantly shorter in MOLE patients compared with SOLE patients. Conclusion: In surgical neonates, MOLE may not prevent cholestasis and should not be considered hepatoprotective. Regardless of ILE source, all surgical neonates should be closely monitored for development of IFALD. To date, there is still no ILE able to prevent IFALD. [ABSTRACT FROM AUTHOR]

Dubin-Johnson syndrome (DJS) is a rare benign autosomal recessive disorder characterized by cholestasis in neonates. The aim of the present study was to describe the clinical characteristics, hepatic profiles, histopathology, gene mutations, and treatment outcomes of neonatal DJS. A multicenter retrospective study was undertaken with patients who had DJS. The authors identified DJS in neonates and reviewed medical records for details. The diagnosis of DJS was based on the presence of unexplained prolonged conjugated hyperbilirubinemia and presence of a mutation in the ATP Binding Cassette Subfamily C Member 2 (ABCC2) gene detected in genomic DNA extracted from circulating blood cells. Eleven children with DJS were identified in the study. The study population comprised eight males and three females. The median age at presentation was 21 days. Dysmorphic features were not recorded in any of the patients. Cholestasis, high serum bile acids, and normal transaminase levels were found in all patients (100%). Serum alkaline phosphatase and gamma glutamyl transferase were elevated in four patients (36%). Hypoalbuminemia and coagulopathy were not noted in these patients. Consanguinity was present in nine patients (82%). All patients had normal abdominal ultrasound findings. Genetic molecular testing showed that 82% of the patients reported a pathogenic variant of the ABCC2 gene defect with the same variant c.2273G> T (Gly 758 val) chromosome 10. All patients were alive without liver transplantation. This is the largest study worldwide describing that neonatal DJS is a benign cholestatic disease with favorable outcomes. Low-grade direct hyperbilirubinemia, normal transaminases, and elevated serum bile acids are the main characteristic findings of DJS. [ABSTRACT FROM AUTHOR]

Background: Neonatal cholestasis (NC) is a major cause of morbidity and mortality in young infants. This study examines the etiology of NC and its outcome during 2 years of follow-up at a tertiary referral center in Bangladesh. Results: Out of 80 cholestatic infants, 60% had intrahepatic cholestasis with a mean age of onset of 12.4±2.8 days and a mean age of admission of 82.4±29.0 days. The remaining 40% were extrahepatic with a mean age of onset of 6.7±2.3 days and a mean age of admission of 94.6±50.4 days. Biliary atresia (BA), idiopathic neonatal hepatitis (INH), and TORCH (Toxoplasma, rubella, cytomegalovirus, and herpes simplex) infection except rubella were the most common causes. After receiving treatment, 46.2% of the cases improved, 23.8% deteriorated with morbidity, and 30% died. The majority of the children with INH, TORCH, choledochal cyst, hypothyroidism, galactosemia, and urinary tract infection (UTI) with sepsis were improved. Significant mortality was found in BA (56.6%), intrahepatic bile duct paucity (PIBD) (100%), and progressive familial intrahepatic cholestasis (PFIC) (100%) whereas the rest of BA (43.4%) live with persistent morbidity. Significant clinical improvement was observed in 37 (46.2%) cases of cholestasis evidenced by decreasing jaundice, change of color of urine from dark to normal color, change of stool color from pale to yellow, and gradual decrease in liver size from hepatomegaly state. In addition, decreasing median total bilirubin, direct bilirubin, alanine transaminase, gamma-glutamyl transferase, and alkaline phosphatase showed biochemical improvement at 2 years follow-up. The age of admission, etiology, and presence of ascites are the predictors of outcomes. Conclusion: BA was the most common cause of extrahepatic while INH and TORCH infection were the most common cause of intrahepatic cholestasis. Majority of children with intrahepatic cholestasis improved but deteriorated with BA and genetic causes. Prompt referral and early diagnosis as well as the etiology of NC were the main determinants of the favorable outcome. [ABSTRACT FROM AUTHOR]

Background Cholestatic liver disease constitutes a large percentage of chronic liver diseases during infancy. Cholestasis is defined as interference with bile formation or flow owing to pathology anywhere between the hepatocyte and the ampulla of Vater. Aim To evaluate the different modalities used for diagnosing cholestasis in infants in Damanhour Medical National Institute (DMNI) to find out the sensitivity and the predictive values of each modality in defining the cause of cholestatic jaundice, whether surgical or medical. Patients and methods This study was a retrospective one which included 153 infants who were referred with cholestasis in first year of life to the Pediatric Hepatology Clinic of the Children's Department (DMNI) from June 2013 to December 2018. The medical records of the 153 infants with confirmed cholestasis were reviewed regarding the history and clinical examination, laboratory data, ultrasound, and liver biopsy. The cases were classified into two groups according to the etiology. Group I comprised (Extrahepatic Biliary Atresia) EHBA, and there were 40 patients in this group. Group II comprised non-EHBA (the medical causes of cholestasis), and there were 113 patients in this group. Results Nearly half (52%) of the patients were females. There were no significant differences regarding sex between EHAB and non-EHBA patients. An enlarged liver was also a common finding, being present in more than 66% of infants, irrespective of the underlying cause. Splenomegaly was more commonly noted in group II (27.43%) versus group I (12.5%), but the differences were not statistically significant. Persistently day stools were observed by 95% of mothers of babies of group I compared with 15% in group II, with a highly significant statistical difference. No significant differences were found between group I and group II regarding most tests of the biochemical profile, except Gamma-glutamyl transferase (GGT) and alkaline phosphatase (AL Ph), as they were significantly higher in group I compared with group II. However, aspartate transaminase (AST), alanine transaminase (ALT), and partial thromboplastin time were significantly higher in group II compared with group I. Conclusion and recommendations It is recommended the use of the developed model, GGT, and AL Ph as first line of investigations, and follow-up for excluding EHBA. Urgent referral of patients to perform a liver biopsy should be done based on the calculated probability of the developed model more than 0.128, GGT more than 500, and Al Ph more than 600. Campaigns to increase awareness among parents and primary care doctors are recommended for early drug and management. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is a challenging liver disease in infancy. Early diagnosis of BA is important for timely hepatoportoenterostomy. We evaluated the age‐specific diagnostic performance of transient elastography (TE) with a liver stiffness measurement (LSM) greater than 7.7 kPa in BA among infants with cholestasis. A total of 61 infants with cholestasis (5‐121 days of age) were enrolled in this prospective follow‐up study; 15 infants were BA. Four age groups were defined (≤30, 31‐60, 61‐90, and 91‐180 days). Picrosirius red staining was performed to quantify the percentage of collagen fibers in liver specimens. The utility of an LSM greater than 7.7 kPa for diagnosis of BA among infants with cholestasis was compared among age groups. In all four groups, TE showed high diagnostic power for BA using the criterion of an LSM greater than 7.7 kPa. Positive predictive values were 100%, 100%, and 100% in the groups aged 30 days or younger, 31 to 60 days, and 61 to 90 days, respectively. Respective negative predictive values were 90.9%, 94.7%, and 100%, and respective diagnostic accuracies were 92.9%, 95.2%, and 100%. The positive predictive value, negative predictive value, and diagnostic accuracy were 100%, 100%, and 100%, respectively, for LSM greater than 8.8 kPa in the group aged 91 to 180 days. The LSM was positively correlated with the percentage of collagen fibers stained by picrosirius red (P = 0.03). Conclusion: In this prospective follow‐up study, TE had good diagnostic accuracy for differentiation of BA from non‐BA cholestasis in infants with cholestasis who were 90 days of age or younger. The LSM was significantly positive correlated with the liver fibrosis status stained by picrosirius red in infants with cholestasis. [ABSTRACT FROM AUTHOR]

Purpose: Although 1p36 deletion syndrome is the most common terminal deletion syndrome, unexplained phenotypic variability still occurs. We aimed to delineate the phenotype of this syndrome in detail and to characterize the phenotype-genotype correlation. Methods: We retrospectively reviewed 15 patients diagnosed with 1p36 deletion syndrome confirmed by chromosomal microarray. Results: All 15 patients revealed delayed attainment of motor milestones and speech. Seven patients (46.7%) never walked alone and only two (13.3%) could express a simple two-word sentence. They all showed subsequent intellectual disability. Two patients with large deletions of both distal and proximal critical regions of the 1p36 region shared severe intellectual disability with Rett syndrome-like behavioral features. Seizures, although frequent (73.3%), were well-controlled except in one patient with infantile spasms. Facial dysmorphism (92.9%) and ventricular mild dilatation with corpus callosum anomaly (46.7%) were common. Heart problems were identified in 14 patients, including structural abnormalities and/or functional problems associated with the gene encoding PR domain-containing protein 16. Two patients developed severe cardiac dysfunction requiring heart transplantation in their late teens. One patient with a 400 Kb deletion partly overlapping with the gene encoding calmodulin-binding transcription activator 1 did not have facial dysmorphism and presented with mild developmental delay and ataxic gait. One patient had a choledochal cyst, which was resected due to neonatal cholestasis. Conclusion: Although the phenotype of 1p36 deletion syndrome is quite consistent with previous reports, additional manifestations such as certain behavioral features, ataxic gait, and severe cardiac dysfunction at an early age should be considered. [ABSTRACT FROM AUTHOR]

Aim of the study: To determine the hepatic interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) levels in infants with neonatal cholestasis (NC) and associated cytomegalovirus (CMV) infection. Material and methods: This study was conducted in 21 infants with NC over a period of 6 months from June 2017 to December 2017 to determine the hepatic IFN-γ and TNF-α levels in infants with NC and associated CMV infection. Results: IFN-γ levels were positive in 16 (80%), low positive in 3 (16%) and negative in 1 (5%) patients. High positive and positive TNF-α levels were seen in 9 (56.3%) patients with positive liver CMV PCR and low positive levels were seen in 7 (43.7%) patients with positive liver CMV PCR (odds ratio [OR] = 2.6). Positive IFN-γ was present in 13 (81.3%) patients with positive liver CMV PCR and low positive or negative IFN-γ was seen in 3 (18.7%) patients with positive liver CMV PCR (OR = 2.2). Six (60%) patients with positive or high positive TNF-α levels in liver tissue had biliary atresia (BA) whereas 7 (77.7%) with low positive TNF-α levels had non-BA neonatal hepatitis (OR = 5.25). Six (37.5%) patients with positive IFN-γ had BA whereas 2 (50%) patients with low positive or negative IFN-γ had BA (OR = 0.6). Conclusions: There is high prevalence of CMV in liver tissues in patients with NC and elevated TNF-α and IFN-γ levels are seen in these patients. Elevated TNF-α is also seen in patients with BA. The association of elevated TNF-α, BA and CMV infection needs to be evaluated further. [ABSTRACT FROM AUTHOR]

Neonatal cholestasis disease (NCD) is a complex and easily mis-diagnosed condition. We analyzed microbiota community structure in feces and measured short-chain fatty acids, bile acids (BAs) and liver function of 12 healthy, 13 NCD, and 13 treated infants after diagnosis. Based on 16S rRNA gene amplicon sequencing and gas-chromatographic-mass-spectrometric analysis of secondary BAs, we identified microbial genera and metabolites that associate with abnormal bile secretion. Streptococcus gallolyticus and Parabacteroides distasonis, and Lactobacillus gasseri had higher relative abundance in healthy and NCD infants respectively. Compared to NCD patients, healthy infants had higher LCA, CDCA and GCDCA fecal concentrations. The three microbial species and three secondary bile acids were selected as potential non-invasive combined biomarkers to diagnose NCD. We propose that microbiota-metabolite combined biomarkers could be used for diagnosis of NCD, and this may contribute to improved early clinical diagnosis of NCD in the future. [ABSTRACT FROM AUTHOR]

Aim of the study: Assessment of hepatic expression of vascular endothelial growth factor A (VEGF-A) in liver tissues of infants with biliary atresia (BA). Material and methods: This retrospective study included 35 infants with BA (BA group), and 38 infants with cholestasis due to causes other than BA (non-BA group). All patients had undergone full history taking, through clinical examination, routine investigations and immunostaining of liver tissue for VEGF-A and cytokeratin 7 (CK7). The diagnosis of BA was confirmed by intraoperative cholangiography. In the non-BA group, other specific laboratory tests according to the expected etiology were done. Results: Most of the BA group showed positive VEGF-A expression with variable degrees in both bile ducts (BDs; 80%), and arterial walls (AWs; 77.2%), while most of the non-BA group showed negative staining of VEGF in both BDs and AWs (89.5% and 86.8% respectively) (p < 0.0001). Positive VEGF expression in the portal structures in both BDs and AWs had 84.9% and 82.19% accuracy; respectively. The majority of BA group showed either grade II of positive cytokeratin-7 expression in liver tissues (45.7%) or grade III (34.3%), while most of the non-BA group showed grade I (71.1%) (p < 0.0001). Positive CK7 expression in > 25% of the liver tissues had 80.8% accuracy in discriminating between BA and non-BA. Conclusions: VEGF-A expression in the portal structures in liver tissues in both BDs and AWs had very good accuracy in discriminating between BA and non-BA patients. [ABSTRACT FROM AUTHOR]

Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma‐glutamyltransferase (GGT) cholestasis. Here, we report whole‐exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 (KIF12). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion: Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children. Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children high gamma‐glutamyltransferase (GGT) cholestasis. Here, we studied 3 children from 2 unrelated consanguineous families with high GGT cholestasis of unclear etiology and found that their underlying liver disease is due to recessive mutations in KIF12, which encodes kinesis family member 12. [ABSTRACT FROM AUTHOR]

1. The present study was conducted to investigate whether brain somatostatin increases feed intake in neonatal chickens. The mediating role of neuropeptide Y receptors on feed intake induced by somatostatin was investigated. 2. In this study, seven experiments were designed, each with four treatment groups (n = 44 in each experiment). In Experiment 1, chicks received control solution and 0.5, 1 and 2 nmol of somatostatin through intracerebroventricular (ICV) injection. In experiments 2, 3 and 4, chickens were ICV injected with control solution and 1.25, 2.5 and 5 μg of B5063 (NPY1 receptor antagonist), SF22 (NPY2 receptor antagonist) and SML0891 (NPY5 receptor antagonist), respectively. In experiment 5, 6 and 7 chickens received ICV injection of B5063, SF22, SML0891, with a co-injection of + somatostatin, control solution and somatostatin. The cumulative feed intake was measured until 120 min post injection. 3. Somatostatin significantly increased feed intake in FD3 chicks. Both B5063 and SML0891 dose-dependently decreased feed intake compared with the control group, while SF22 led to a dose-dependent increase in feed intake. In addition, the hyperphagic effect of somatostatin significantly decreased with co-injection of B560 plus somatostatin (p < 0.05), but SF22 and SML0891 had no effect on feed intake induced by somatostatin in chicks (p > 0.05). 4. Based on the results of this study, it is likely that somatostatin increased feed intake and NPY1 receptor acts as a mediator in hyperphagic effect of somatostatin in neonatal chicks. [ABSTRACT FROM AUTHOR]

Various atypical manifestations have been described in acute viral hepatitis (AVH). We evaluated the prevalence, clinical features, response to treatment and outcome of various atypical manifestations of AVH in children. Consecutive children (≤ 18 years) with AVH due to hepatitis A, B, or E were studied while patients with acute or acute on chronic liver failure were excluded. Diagnosis of atypical manifestations was based on standard criteria. A total of 477 children with AVH (median age 7.0 (5-11) years, 74% boys) were seen; 22% (n = 106) had atypical manifestations. Prolonged cholestasis was the most common (11%), followed by ascites (7%), intravascular hemolysis (3%), relapsing hepatitis (2%), acute pancreatitis (1.3%), and thrombocytopenia (0.7%). Atypical manifestations were more common in HAV as compared to HBV (30% vs. 3%, p = 0.00) and HEV (30% vs. 15%, p = 0.07). Prolonged cholestasis was significantly more common in older children (20% in > 10 years vs. 9% in 6-10 years ; p = 0.009 and 5% in 0-5 years of age [p < 0.000]). Ascites was more common in younger children, although not significant. All patients recovered with supportive treatment.Conclusions: Twenty-two percent of children with AVH have atypical manifestations, more often with HAV infection, and prolonged cholestasis is most common. Recognition of these manifestations ensures correct diagnosis and treatment. What is Known: • Acute viral hepatitis is a major public health problem in developing countries. • There is limited information about atypical manifestations which may lead to unnecessary investigations, delayed diagnosis and morbidity. What is New: • Atypical manifestations are common in children, seen most often with HAV infection, and prolonged cholestasis is most common. • Prompt recognition of these manifestations helps in early diagnosis, appropriate management, and preventing unnecessary investigations. • Ensure follow-up until complete recovery and not to miss underlying chronic liver disease. [ABSTRACT FROM AUTHOR]

Background and Aims: Breast milk jaundice (BMJ) is common and benign, but neonatal cholestasis (NC) is rare and not benign, so early differentiation between NC and non-NC jaundice is important and may facilitate diagnosis and treatment. Gut microbiota plays an important role in enterohepatic circulation, which in turn plays an important role in the secretion of bilirubin. We aimed to determine the composition of gut microbiota in patients with NC and BMJ, and to identify the gut microbiota composition associated with NC and BMJ.Methods: Data on age, gender, delivery, feeding mode, serum total bilirubin, direct bilirubin, and liver function were collected for NC patients, BMJ patients and healthy controls, respectively. Shotgun metagenomic sequencing and metagenome-wide association were performed.Results: Forty NC patients, 16 patients affected by BMJ, and 14 healthy controls (CON) without jaundice were enrolled. A significant increase in species richness, especially Bacteroides, was found in NC patients. The abundances of potentially pathogenic species and KEGG orthologies (KOs) of virulence factor genes were positively correlated with serum bilirubin level. The abundances of nine species of Bifidobacterium and three KOs of galactose metabolism were significantly decreased in the jaundice group (NC and BMJ) and were negatively correlated with serum bilirubin level.Conclusions: The gut microbiota in NC patients is characterized by a significant increase in species richness, possibly due to the proliferation of potentially pathogenic species. Additionally, the gut microbiota in jaundice patients is characterized by a decreased abundance of Bifidobacterium. Decreased Bifidobacterium has been associated with elevated bilirubin and abnormal gut microbiota galactose metabolic pathway. Further, ten bacteria species were identified as potential biomarker of jaundice.Key Points: Question Is there any alteration of gut microbiotain neonatal cholestasis patients? Does gut microbiota have any involvement in the occurrence of neonatal cholestasis or breast milk jaundice? Findings The alteration of gut microbiota in neonatal cholestasis patients mainly manifested as a significant increase in species richness and an increased abundance of potentially pathogenic species, while the main manifestation in jaundice patients was a significant decrease in Bifidobacterium which may be involved in the metabolism of bilirubin through the galactose metabolic pathway. Meaning The results suggest that an imbalance of gut microbiota exist in neonatal cholestasis and breast milk jaundice patients, primarily in the form of a substantial reduction in the abundance of Bifidobacterium, suggesting the possibility of intervention treatment for neonatal cholestasis and breast milk jaundice by supplementing probiotics. [ABSTRACT FROM AUTHOR]

Purpose: Infants with Alagille syndrome (AGS) frequently develop neonatal cholestasis, and some AGS infants who suspected of biliary atresia subsequently undergo the Kasai operation with the diagnosis of biliary atresia. The aim of this study was to investigate the effect of the Kasai operation on liver and patient outcomes among AGS patients, using a meta-analysis.Methods: A systematic review and meta-analysis of studies describing the outcomes of AGS patients with/without the Kasai operation were conducted. The analyzed outcomes were liver transplantation, not living with the native liver, and mortality for any reason.Results: We identified 6 studies (394 AGS patients). All studies were retrospective cohort or case-control studies. The incidences of liver transplantation, not living with the native liver, and mortality were significantly higher in AGS patients who underwent the Kasai operation than in those who did not undergo the Kasai operation (odds ratio: 6.46, 95% CI 3.23-12.89, p < 0.00001; odds ratio: 25.88, 95% CI 2.83-236.84, p < 0.004; odds ratio: 15.05, 95% CI 2.70-83.93, p = 0.002, respectively).Conclusion: The Kasai operation was associated with poor outcomes in AGS patients. It remains unclear if the Kasai operation directly deteriorates liver and patient outcomes in AGS patients. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to examine perinatal outcomes associated with cholestasis of pregnancy according to bile acid level and antenatal testing practice.Study Design: Retrospective cohort study of women with symptoms and bile acid testing from 2005 to 2014. Women were stratified by bile acid level: no cholestasis (<10 μmol/L), mild (10-39 μmol/L), moderate (40-99 μmol/L), and severe (≥100 μmol/L). The primary outcome was composite neonatal morbidity (hypoxic ischemic encephalopathy, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or death).Results: 785 women were included; 487 had cholestasis (347 mild, 108 moderate, 32 severe) and 298 did not. After controlling for gestational age (GA), severe cholestasis was associated with the composite neonatal outcome (aRR 5.6, 95% CI 1.3-23.5) and meconium-stained fluid (aRR 4.82, 95%CI 1.6-14.2). Bile acid levels were not correlated with the frequency of testing (p = .50). Women who underwent twice weekly testing were delivered earlier (p = .016) than women tested less frequently, but the difference in GA was ≤4 d. Abnormal testing prompting delivery was uncommon. Among women with cholestasis, there were three stillbirths. One of these women was undergoing antenatal testing, which was normal 1 d prior to the fetal demise.Conclusion: Severe cholestasis is associated with neonatal morbidity which antenatal testing may not predict. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to examine perinatal outcomes associated with cholestasis of pregnancy according to bile acid level and antenatal testing practice.Study Design: Retrospective cohort study of women with symptoms and bile acid testing from 2005 to 2014. Women were stratified by bile acid level: no cholestasis (<10 μmol/L), mild (10-39 μmol/L), moderate (40-99 μmol/L), and severe (≥100 μmol/L). The primary outcome was composite neonatal morbidity (hypoxic ischemic encephalopathy, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or death).Results: 785 women were included; 487 had cholestasis (347 mild, 108 moderate, 32 severe) and 298 did not. After controlling for gestational age (GA), severe cholestasis was associated with the composite neonatal outcome (aRR 5.6, 95% CI 1.3-23.5) and meconium-stained fluid (aRR 4.82, 95%CI 1.6-14.2). Bile acid levels were not correlated with the frequency of testing (p = .50). Women who underwent twice weekly testing were delivered earlier (p = .016) than women tested less frequently, but the difference in GA was ≤4 d. Abnormal testing prompting delivery was uncommon. Among women with cholestasis, there were three stillbirths. One of these women was undergoing antenatal testing, which was normal 1 d prior to the fetal demise.Conclusion: Severe cholestasis is associated with neonatal morbidity which antenatal testing may not predict. [ABSTRACT FROM AUTHOR]

Introduction and aim. Neonatal cholestasis constitutes for 19 to 33% of all chronic liver disease in India. Cholestasis leads to fibrosis of liver and ultimately cirrhosis. There are various methods of diagnosis of fibrosis of liver like fibroscan, aspartate transaminase to platelet ratio index (APRI) index, FIB-4, fibro index, forns index, heap score, magnetic elastography. Here we are comparing APRI index with METAVIR index in patients with neonatal cholestasis without biliary atresia and determining whether APRI index can be used as a tool to determine fibrosis in these patients. Material and methods. Patients with neonatal cholestasis without biliary atresia were included in the study. This retrospective analysis was done between 2009 and 2015. All patients underwent a liver biopsy and METAVIR index was calculated. APRI at the time of liver biopsy was determined. Results. Forty-eight patients were included in this study with mean age of 3.5 ± 2.8 months with a male: female ratio of 35:13. Metavir Index F0 was seen in was 32 (66.67%) patients, F1 in 6(12.5%), F2 in 4(8.33%), F3 in 0 and F4 in 6(12.5%) patients respectively. Mean APRI for F0-F3 was 1.38 and for F4 was 3.74 respectively. With an APRI of 1.38, the sensitivity and specificity to detect fibrosis/cirrhosis was 100% and 21.43% respectively. Conclusion. APRI is not an effective tool to measure fibrosis or cirrhosis in patients with non-BA neonatal cholestasis in Indian children. [ABSTRACT FROM AUTHOR]

Objective: To study the correlation between vitamin B12 deficiency and hyperbilirubinemia and cholestasis in infants. Methods: The study group consisted of 215 infants who were tested for serum B12 and bilirubin levels out of 335 cases referred to the Centre from June 2011 to 2016 as a part of the screening program established by the Ministry of Health. The following information was obtained from the case files: demographic data; background; family history; serum vitamin B12, folate, plasma homocysteine, and urine methylmalonic acid (MMA) levels; and direct, indirect, and total bilirubin levels. Results: About 48.8 percent of cases had vitamin B12 deficiency. No significant differences were found when those cases with vitamin B12 deficiency and those without vitamin B12 deficiency were compared in terms of total, direct, or indirect bilirubin levels. Only two cases (0.9 percent) had cholestasis. Conclusion: The study suggests vitamin B12 deficiency is a common phenomenon (48.4 percent), similar to what has been suggested by other studies conducted in Turkey. Therefore, the presence of vitamin B12 deficiency in cases with cholestasis or hyperbilirubinemia may show an association. To prove the correlation between them, more studies are required. [ABSTRACT FROM AUTHOR]

Background: Parenteral nutrition-associated cholestasis (PNAC) is a major cause of morbidity and mortality in premature infants. Early predictors of PNAC would have clinical value. We sought to evaluate risk factors and liver function testing as predictors of PNAC in premature infants with intestinal perforation.Methods: Medical records of infants with a gestational age <34 weeks, birth weight <2000 g, and intestinal perforation due to either necrotizing enterocolitis or spontaneous intestinal perforation were reviewed. We analyzed clinical data and the maximum values of the aspartate aminotransferase (AST) to platelet ratio index (APRI), alanine aminotransferase (ALT), AST to ALT ratio, and total bilirubin (TB).Results: Sixty infants were identified, 17 infants with PNAC and 43 infants without PNAC. Sepsis, time to initiation of enteral feeds after perforation, and duration of PN were associated with PNAC. Within 2 weeks following intestinal perforation, APRI, ALT, and TB each differed significantly between infants who later developed PNAC and those that did not. The best APRI cut-point was 0.4775 within 2 weeks after perforation (area under the receiver operating characteristic curve, 0.90; positive predictive value, 85%; and negative predictive value, 87%); the cut-point for ALT was 13.5 (0.90, 85%, 84%), and the cut-point for TB was 3.55 (0.82, 69%, 83%), respectively, at 2 weeks after perforation. AST to ALT ratio did not differ between groups.Conclusions: APRI and ALT had reasonable predictive value for PNAC in premature infants with intestinal perforation, with the APRI the best predictor within 2 weeks after perforation. [ABSTRACT FROM AUTHOR]

Introduction: Biliary Atresia (BA) and Neonatal Hepatitis (NH) are common causes of Neonatal Cholestasis (NC). There is a high degree of overlap between clinical and other investigational characteristics of BA and NH. Aim: To study the histopathological features of liver biopsies in cases of NC syndromes and to apply a histopathological scoring system in differentiating BA from other causes of NC. Materials and Methods: This study included 51 cases of NC (BA=25, NH=26) from Jan 2010 to June 2014. A scoring system, devised by Lee WS and Looi LM was applied to all the cases. Clinical, biochemical, Hepatobiliary scan (HIDA scan) and Peroperative Cholangiogram (POC) details of all the patients were collected. Results: Liver biopsy showed moderate to marked bile ductular proliferation in 24 (96%), bile plugging in 13 (52%), portal expansion in >50% of portal tracts in 19 (76%) and moderate/severe lymphocytic infiltration in 15 (60%) cases of BA. Diffuse giant cell transformation and hepatocytic swelling were present in 19 (73%) and 22 (85%), respectively of NH. Score of =7 was helpful in differentiating BA from NH with 92% sensitivity and 96% specificity. Non-excretion of dye in the HIDA scan had 91% sensitivity and 65% specificity for the score of =7 which favoured the diagnosis of BA. POC was taken as the gold standard. Conclusion: A detailed histomorphology of liver biopsy along with a Lee and Looi score of =7 was helpful in differentiating BA from NH. [ABSTRACT FROM AUTHOR]

Aim of the study: Assessment of the expression of cluster of differentiation (CD)3, CD4, and CD8 T cells in biliary atresia (BA) cases in comparison to neonatal cholestasis other than BA. Material and methods: This study included 79 patients: 34 patients with BA (BA group) and 35 patients with neonatal cholestasis due to causes other than BA (cholestasis group), and 10 normal liver donor as a control group. Immunohistochemical staining or CD3, CD4, and CD8 T cells in liver tissues for the 3 groups were evaluated. Results: Presence of clay stool, high gamma-glutamyl transferase levels, thrombocytosis, and non-contractibility of the gallbladder was the main clinical, laboratory, and radiological findings, distinguishing BA from other disorders causing neonatal cholestasis. Portal ductular proliferation, bile plugs in portal ductules, and advanced grades of fibrosis were more predominant in liver biopsy specimens of BA patients. The CD3+, CD4+, and CD8+ expression in patients with BA were significantly higher than in both cholestasis and control groups, while it was comparable in the cholestasis and control groups, with cutoff values of 25, 12, and 2.5 cells/portal tract, respectively, differentiating between BA and cholestatic patients. Conclusions: Immune-mediated destruction of bile ducts is incriminated in the pathogenesis of BA. Lymphocytic infiltrate in portal tract is primarily composed of CD3, CD4, and CD8 T cells. Immunostaining of liver tissue for CD3, CD4, and CD8 T cells can help in ensuring diagnosis of BA. [ABSTRACT FROM AUTHOR]

Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder with a great variation in clinical spectrum and age at presentation. Clinical features of 10 NPC patients who presented in the newborn period between 1993 and 2015 at our center were retrospectively analyzed. Males and females were equally distributed; there was a history of parental consanguinity (n = 8) and first-degree relative with NPC (n = 3). Patients were symptomatic between 1 and 10 days (mean 3.6 ± 2.6 days). Age at diagnosis was between 1 and 30 days (mean 14.6 ± 13.3 days). Laboratory work-up included bone marrow aspiration (n = 8) and/or filipin staining (n = 4). Confirmation was done by molecular analysis, indicating NPC1 (n = 8) and NPC2 (n = 2) mutations. All patients had neonatal cholestasis and hepatosplenomegaly. Pulmonary involvement (n = 9) and fetal ascites (n = 2) were additional accompanying features. All but one died due to pulmonary complications (n = 6) and liver insufficiency (n = 3) between 1.5 and 36 months of age (mean 8.1 ± 10.8 months). Currently, one patient is alive at the age of 11 months without any neurological deficit.Conclusions: Neonatal presentation is a rare form of NPC with exclusively visceral involvement in the newborn period and poor prognosis leading to premature death due to pulmonary complications and liver failure. What is known: • Neonatal presentation is a rare form of NPC with exclusively visceral involvement in the newborn period and poor prognosis leading to premature death. • Progressive liver disease is the most common cause of death among neonatal-onset NPC patients. What is new: • Natural course of neonatal-onset NPC may show variations. • Pulmonary involvement should be considered as an important cause of death in neonatal-onset cases, and appropriate precautions should be taken to prevent complications of respiratory insufficiency and airway infections. [ABSTRACT FROM AUTHOR]

The article describes the case of a male infant with faltering growth, jaundice and liver dysfunction and was diagnosed with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), an autosomal recessive disorder. It highlights improvements on the patient following dietary intervention including resolution of his jaundice and biochemical and metabolic abnormalities and weight gain. Clinical manifestations of citrin deficiency and effectiveness of dietary management are discussed.

Biliary atresia is a devastating biliary disease of neonates that results in liver transplantation for the vast majority. The etiology of biliary atresia is unknown and is likely multifactorial, with components of genetic predisposition, environmental trigger and autoimmunity contributing to disease pathogenesis. This review highlights recent work related to investigations of disease pathogenesis in biliary atresia. [ABSTRACT FROM AUTHOR]

Introduction: Due to a peculiar age-dependent increased susceptibility, neonatal cholestasis affects the liver of approximately 1 in every 2500 term infants. A high index of suspicion is the key to an early diagnosis, and to implement timely, often life-saving treatments. Even when specific treatment is not available or curative, prompt medical management and optimization of nutrition are of paramount importance to survival and avoidance of complications. Areas covered: The present article will prominently focus on a series of newer diagnostic and therapeutic options of cholestasis in neonates and infants blended with consolidated established paradigms. The overview of strategies for the management reported here is based on a systematic literature search published in English using accessible databases (PubMed, MEDLINE) with the keywords biliary atresia, choleretics and neonatal cholestasis. References lists from retrieved articles were also reviewed. Expert commentary: A large number of uncommon and rare hepatobiliary disorders may present with cholestasis during the neonatal and infantile period. Potentially life-saving disease-specific pharmacological and surgical therapeutic approaches are currently available. Advances in hepatobiliary transport mechanisms have started clarifying fundamental aspects of inherited and acquired cholestasis, laying the foundation for the development of possibly more effective specific therapies. [ABSTRACT FROM PUBLISHER]

Introduction Nonobstructive cholestasis after pediatric liver transplantation is a common diagnostic and therapeutic dilemma. We describe a girl with neonatal cholestasis because of progressive familial intrahepatic cholestasis 2 (PFIC-2) and presence of a homozygous splice site mutation in the ABCB11 gene. Liver transplantation was performed because of end-stage liver disease at the age of 6. Cholestasis with normal gamma-glutamyl transferase (GGT) developed 8 years after liver transplantation. A liver biopsy showed canalicular cholestasis and giant cell hepatitis without evidence of rejection, mimicking PFIC-2. Immunofluorescence staining of normal human liver sections with patient's serum revealed reactivity toward a canalicular epitope, which could be identified as bile salt export pump (BSEP) using BSEP–yellow fluorescent protein (YFP) transfected cells. Our patient developed a recurrence of a PFIC-2 phenotype due to production of antibodies against BSEP (alloimmune BSEP disease [AIBD]). Intensification of immunosuppressive therapy as well as antibody treatment with plasmapheresis and Rituximab were initiated, leading to stabilization of the clinical condition and depletion of anti-BSEP antibodies in serum. However, after 1 year liver transplantation was necessary again because of end-stage liver insufficiency. Afterward, immunomodulatory treatment consisted of tacrolimus, mycophenolate mofetil, prednisone, immunoadsorption, and high-dose immunoglobulin therapy (1 g/kg/d). Conclusion Cholestasis after liver transplantation may indicate an AIBD with a PFIC-2 phenotype. Besides enhancement of immunosuppressive therapy, an antibody depletion with plasmapheresis, immunoadsorption, immunoglobulins, and B-cell depletion represents a therapeutic option. [ABSTRACT FROM AUTHOR]

Congenital hepatic fibrosis is characterized by hepatic fibrosis, portal hypertension, and renal cystic disease. Typical presentation of congenital hepatic fibrosis is in the form of portal hypertension, in adolescents and young adults. We present an unusual case of neonatal cholestasis with rapid deterioration within first 4 months of life, who was diagnosed to have congenital hepatic fibrosis with polycystic kidney disease on autopsy. [ABSTRACT FROM AUTHOR]

Recently, bi-allelic mutations in cytosolic isoleucyl- tRNA synthetase ( IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole-exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology. Furthermore, we provide functional data on two novel missense substitutions and expand the phenotype to include mild developmental delay, skin hyper-elasticity, and hypervitaminosis D. [ABSTRACT FROM AUTHOR]

Introduction: Optimizing outcome in biliary atresia (BA) requires timely diagnosis. Cholestasis is a presenting feature of BA, as well as other diagnoses (Non-BA). Identification of clinical features of neonatal cholestasis that would expedite decisions to pursue subsequent invasive testing to correctly diagnose or exclude BA would enhance outcomes. The analytical goal was to develop a predictive model for BA using data available at initial presentation. Methods: Infants at presentation with neonatal cholestasis (direct/conjugated bilirubin >2 mg/dl [34.2 μM]) were enrolled prior to surgical exploration in a prospective observational multi-centered study (PROBE–NCT00061828). Clinical features (physical findings, laboratory results, gallbladder sonography) at enrollment were analyzed. Initially, 19 features were selected as candidate predictors. Two approaches were used to build models for diagnosis prediction: a hierarchical classification and regression decision tree (CART) and a logistic regression model using a stepwise selection strategy. Results: In PROBE April 2004-February 2014, 401 infants met criteria for BA and 259 for Non-BA. Univariate analysis identified 13 features that were significantly different between BA and Non-BA. Using a CART predictive model of BA versus Non-BA (significant factors: gamma-glutamyl transpeptidase, acholic stools, weight), the receiver operating characteristic area under the curve (ROC AUC) was 0.83. Twelve percent of BA infants were misclassified as Non-BA; 17% of Non-BA infants were misclassified as BA. Stepwise logistic regression identified seven factors in a predictive model (ROC AUC 0.89). Using this model, a predicted probability of >0.8 (n = 357) yielded an 81% true positive rate for BA; <0.2 (n = 120) yielded an 11% false negative rate. Conclusion: Despite the relatively good accuracy of our optimized prediction models, the high precision required for differentiating BA from Non-BA was not achieved. Accurate identification of BA in infants with neonatal cholestasis requires further evaluation, and BA should not be excluded based only on presenting clinical features. [ABSTRACT FROM AUTHOR]

Background: Intestinal failure-associated liver disease (IFALD) remains a serious problem in the treatment of infants with nutritional problems and short bowel syndrome.Methods: A review of the recent literature from 2010 to 2016, concentrating on articles related to the pathophysiology of IFALD and to outcomes of novel nutritional and pharmacological therapies for neonatal cholestasis in the post-surgical neonate.Results: The pathophysiology of IFALD relates to an increase sensitivity of the neonatal liver to cholestasis in the non-fed state; prolonged cholestasis almost inevitably results in liver damage which will progress from fibrosis to cirrhosis. Clinically discerned risk factors include premature birth, inflammation, sepsis, disruption of the enterohepatic circulation by creation of a proximal stoma, and the duration and type of parenteral nutritional support. Within the hepatocyte, the regulatory enzyme farsanoid receptor X (FXR) appears to play a pivotal role in the development of cholestasis. Recent studies have shown that its activity is suppressed by sepsis, and by plant phytosterols found in soy-based lipid preparations. This paradigm is reflected in the emerging consensus for the care of post-surgical neonates, which is based around a multi-disciplinary team approach. Using an algorithm-driven approach, an appropriate balance between caloric support and prevention of IFALD can be achieved.Conclusions: Further prospective studies are required to further refine the optimal sequence of use of these therapies and the long-term effects on neurological development and hepatic function. However, with optimal care, the number of IF patients progressing to end-stage liver disease because of IFALD should be very low. [ABSTRACT FROM AUTHOR]

Alagille Syndrome (ALGS) is a rare autosomal dominant disorder that affects multiple organ systems. Cholestasis as a result of a paucity of intrahepatic bile ducts and congenital heart defects are the two most common features of ALGS. We describe a case of ALGS with novel mutations of JAG1 and NOTCH2 genes in a newborn girl with complex congenital heart disease, bilateral dysplastic kidneys, and malrotation with volvulus. [ABSTRACT FROM AUTHOR]

Background/aim: Maternal, fetal, and neonatal outcomes in parturients with intrahepatic cholestasis of pregnancy (ICP) have been retrospectively documented. We aimed to present pregnancy outcomes of parturients with ICP who underwent delivery. The study was conducted during a 1-year period. Materials and methods: After ethics committee approval, data from 1 January to 31 December 2015 were collected to identify parturients with ICP. Results: Ten out of 37 patients underwent normal spontaneous vaginal delivery (NSVD), and the remaining 27 parturients underwent cesarean section (CS). Five of 27 parturients underwent nonelective cesarean section, while 22 had elective cesarean delivery. As for NSVD deliveries, only one parturient received combined spinal and epidural anesthesia (CSE) for labor. Neuraxial (n = 22 for spinal and n = 1 for CSE) and general anesthesia (n = 4) rates for CSs were 85% and 15%, respectively. Approximately 96% of neuraxial anesthesia choices were spinal anesthesia. Nearly 18.5% of CSs were not elective. Adverse outcomes included 2 preterm births, 2 preterm labors, 2 newborns with hepatitis, and one perinatal fetal death. Conclusion: Parturients with ICP who had normal coagulation parameters despite increased liver enzymes preoperatively underwent cesarean delivery under spinal anesthesia without complication. Although maternal outcomes were generally positive, adverse fetal and neonatal outcomes are more likely to occur, particularly in cases with severe ICP. [ABSTRACT FROM AUTHOR]

Jaundice and pale stools are major indicators of neonatal liver disease. Prognosis depends on timely diagnosis and management. We evaluated the clinical practices among healthcare professionals concerning jaundiced newborns and their ability to recognize pale stools. We supplied a questionnaire and a panel with eight photographs of stools, both locally validated, to physicians and nurses of the National Healthcare Service. Analysis was conducted according to professional status, specialization and years of experience of professionals and level of healthcare. Questionnaires were administered to 266 participants (100 physicians, 166 nurses). The decision to send patients to medical observation depended on the intensity of jaundice for a significant percentage of nurses. Concerning jaundiced newborns breastfed and otherwise healthy, 28.9% of physicians would never request a conjugated bilirubin assay, and only 43.3% would request it after 14 days old; for those with other signs/symptoms of disease, only 69.1% of physicians would request it immediately. Multiple linear regression analysis identified specialization as an independent variable significantly associated with the ability to recognize pale stools.Conclusion: A significant percentage of healthcare professionals assumed clinical practices that preclude the timely recognition of cholestasis/pale stools, reinforcing the idea of educational needs. Specialization, rather than years of experience of professionals, was associated with better skills and practices. What is Known: • Neonatal cholestasis is a condition with some rare underlying entities having high mortality and morbidity. Early diagnosis is crucial to improve prognosis. Yet, many cases remain late recognized and referred. • Studies evaluating the ability of healthcare professionals to recognize neonatal cholestasis are scarce. What is New: • In this study, a significant percentage of professionals assumed clinical practices that preclude timely recognition of neonatal cholestasis and pale stools, reinforcing the idea of educational needs. • Specialization of professionals was associated with better skills and practices. [ABSTRACT FROM AUTHOR]

Jaundice in the newborn period can be physiologic and is often due to benign causes. Jaundice due to conjugated hyperbilirubinemia extending beyond the second week of life may be an early sign of several cholestatic or metabolic liver diseases, and it requires logical and timely analysis so that specific treatments can be initiated. Alpha-1 antitrypsin deficiency is the most common genetic cause of pediatric liver disease and transplantation, and it must be considered when evaluating cholestatic infants. Here, we present an unusual case of alpha-1 antitrypsin deficiency with severe infantile cholestasis and rapid decompensation in the first 4 months of life, where in-depth but timely diagnosis was crucial for the appropriate intervention to take place. [ABSTRACT FROM AUTHOR]

Background/Aims: The safety of the human body is maintained by effective monitoring of the mucosal surface integrity and protection against potentially harmful compounds. This function of the gut called intestinal barrier function can be affected by cholestasis and the absence of bile in the intestinal lumen. We aimed to determine whether the gut barrier integrity is impaired in infants with cholestasis by evaluation of the intestinal fatty acid binding proteins (I-FABP) and ileal bile acid binding protein (I-BABP) as markers of intestinal epithelial cell damage and plasma D-lactate level as a marker of gut wall permeability. Methods: This case-control study included 53 infants with cholestasis and 29 controls. Serum levels of I-FABP, I-BABP, and D-lactate were measured in all subjects. Results: Both groups of patients with neonatal hepatitis and biliary atresia showed significantly higher levels of I-FABP and I-BABP than the controls. There were no differences in the serum D-lactate level between the cases and controls. There was no difference between the two groups of patients (I and II) regarding any of the parameters studied. No significant correlations between serum levels of I-FABP, I-BABP, or D-lactate and total or direct bilirubin levels were found in the cholestatic infants. Conclusions: The intestinal epithelial barrier integrity is breached nearly in all parts of the intestine in infants with cholestasis. Further research is recommended to determine the impact of this finding on the management of these infants. The relationship between physical intestinal barrier damage and its functional failure remains subject for further research. [ABSTRACT FROM AUTHOR]

Estrogen-induced cholestasis, known as intrahepatic cholestasis of pregnancy (ICP), is an estrogen-related liver disease that is widely recognized as female or pregnancy-specific. Our previous findings showed that the synthetic estrogen, 17α-ethinylestradiol (EE), induced cholestatic injury through ERK1/2-LKB1-AMP-activated protein kinase (AMPK) signaling pathway and its mediated suppression of farnesoid X receptor (FXR). To investigate the role played by bile acids in EE-induced cholestasis, we evaluated the effects of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) on sandwich cultured rat primary hepatocytes (SCRHs) and an in vivo rat model. Our results showed that, both CDCA and UDCA significantly induced time- and concentration-dependent reduction in AMPK phosphorylation in SCRHs. Despite having different effects on FXR activation, CDCA and UDCA both inhibited EE-induced AMPK activation, accompanied with the up-regulation of FXR and its downstream bile acid transporters. However, although DCA activates FXR and induces SHP, it was unable to alleviate EE-induced FXR suppression and further aggravated EE-induced cholestasis. We further demonstrated that both CDCA and UDCA, but not DCA, activated cyclic AMP dependent protein kinase (PKA) in SCRHs and the livers of male rats (8 weeks old) liver. Furthermore, PKA antagonist, H89, blocked the AMPK inhibition by CDCA and UDCA, and pharmacological and genetic activation of PKA suppressed EE-induced AMPK activation and its downstream effects. Collectively, these results suggest that CDCA and UDCA protect against estrogen-induced cholestatic injury via PKA signaling pathway and up-regulation of EE-suppressed FXR, which suggests a potential therapeutic target for ICP. [ABSTRACT FROM AUTHOR]

Background: Once it is established that a jaundiced infant has direct hyperbilirubinemia, the principal diagnostic concern is to differentiate hepatocellular from obstructive cholestasis. Traditional tests such as ultrasonography, percutaneous liver biopsy and technetium 99 m hepatobiliary iminodiacetic acid (HIDA) scan are often not sufficiently discriminating. Definitive exclusion of biliary atresia (BA) in the infant with cholestatic jaundice usually requires mini-laparotomy and intra-operative cholangiography. This approach has many drawbacks because those sick infants are subjected to a time-consuming procedure with the probability of negative surgical exploration.Aim Of the Study: The aim of this study was to determine the feasibility of laparoscopic-guided cholecystocholangiography (LGCC) and its accuracy and safety in the diagnosis of BA and thus preventing unnecessary laparotomy in infants whose cholestasis is caused by diseases other than BA.Patients and Methods: Twelve cholestatic infants with direct hyperbilirubinemia subjected to LGCC (age, 7-98 days; mean, 56 days) after ultrasound scan and (99 mTc) HIDA scan and percutaneous liver biopsy failed to provide the definitive diagnosis.Results: One patient had completely absent gall bladder (GB) so the laparoscopic procedure was terminated and laparotomy was done (Kasai operation). Four patients had small size GB; they underwent LGCC that showed patent common bile duct with atresia of common hepatic duct, so laparotomy and Kasai operation was performed. Seven patients had well-developed GB, LGCC revealed patent biliary tree, so laparoscopic liver biopsies were taken for histopathology. Five of those patients had neonatal hepatitis, and two had cholestasis as a complication of prolonged TPN. No perioperative complications or mortalities were recorded.Conclusion: When the diagnosis neonatal cholestasis remains elusive after traditional investigations, LGCC is an accurate and simple method for differentiating BA from hepatocellular causes. [ABSTRACT FROM AUTHOR]

The article presents facts regarding diagnosis of neonatal Cholestasis. Topics of discussion includes facts like it is usually misdiagnosed with breast fed jaundice or breast milk jaundice, it can be identified by fractionating the direct serum bilirubin levels and once diagnosed, treatable causes like congenital disorders, endocrine diseases or urinary tract infections should be identified.

Background: There is deficiency of data about congenital heart defects (CHDs) in cholestatic disorders of infancy other than Alagille syndrome (AGS). We aimed to define the prevalence and types of CHDs in infants with various causes of cholestatic disorders of infancy.Methods: This cross-sectional study was conducted on 139 infants presenting with cholestasis whether surgical or non-surgical. The study was carried out at the Pediatric Hepatology Unit, Cairo University Children's Hospital, Egypt. Full examination and investigations were done in an attempt to reach an aetiologic diagnosis for cholestasis, in addition to a comprehensive echocardiographic study.Results: The age at the onset of cholestasis ranged from 1 day to 7 months. Males constituted 61.2%. Biliary atresia (BA) was diagnosed in 39 patients (28%), AGS in 16 patients (11.5%), 27 patients had miscellaneous diagnoses and 57 cases had indeterminate aetiology. CHDs were detected in 55 patients (39.5%). Shunt lesions were detected in 24 patients (43.6%), pulmonary stenosis in 18 patients (32.7%) and combined lesions in 9 patients (16.4%). Three patients (5.5%) had abnormal cardiac situs. Only seven patients had clinical presentation suggestive of CHD. CHDs were detected in 14 patients with BA (35.9%), 15 patients with AGS (93.7%) and 26 patients in the remaining group (30.9%).Conclusion: CHDs are not uncommon among cholestatic infants and are mostly asymptomatic. Echocardiographic examination of cholestatic infants is recommended particularly for patients with BA before undergoing hepatic portoenterostomy as presence of CHD may impact the anaesthetic planning and affect the outcome of hepatobiliary surgery. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick disease type C (NPC) is a rare lipid storage disorder characterized by progressive neurological deterioration. Diagnosing NPC is challenging as clinical signs and symptoms are variable and non-specific. Two oxysterols, cholestane-3β,5α,6β-triol (triol) and 7-ketocholesterol (7KC), have been proposed as biomarkers for aiding diagnosis of NPC. This study evaluated the use of triol and 7KC as biomarkers in cholestatic neonates with suspected NPC. Methods: Plasma triol and 7KC were analysed as dimethylglycine esters using an liquid chromatography -- tandem mass spectrometry (LC-MS/MS) assay in selected neonates with severe cholestasis and suspected NPC (n = 7), adults with cholestasis (n = 15), patients with confirmed NPC (positive controls; n = 11 [one child and 10 adults]), healthy subjects (negative controls; n = 40 [20 children and 20 adults]), and cholestatic adults (comparative reference; n = 15). The LC-MS/MS method was subjected to a number of tests for accuracy and consistency. Results: Triol and 7KC levels were substantially and significantly increased in NPC positive patients compared with healthy controls (p < 0.001). However, positive results markedly increased levels of both oxysterols) were identified in 6/7 (86%) neonates with cholestasis. Genetic testing confirmed NPC only in one neonate who had increased triol and 7KC, and increased oxysterol levels among neonates with no identified NPC gene mutations were considered likely due to biliary atresia (BA). Conclusions: While the potential of oxysterols as NPC biomarkers has been well evaluated in older patient populations (without cholestasis), our data suggest that cholestasis might represent a pitfall in oxysterol measurements intended to aid diagnosis of NPC in affected patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the correlation between four serum biomarkers of liver fibrosis and liver function in infants with cholestasis. A total of 30 infants with cholestasis and 20 healthy infants were included in the study. Biochemical assays based on the initial rate method and colorimetric assays were conducted to determine the levels of liver function markers in the serum [such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), γ-glutamyl transferase (γ-GT), cholinesterase (CHE) and total bile acids (TBA)] and four serum biomarkers of liver fibrosis were measured using radioimmunoassays [hyaluronic acid (HA), procollagen type III (PCIII), laminin (LN) and collagen type IV (cIV)]. The serum levels of ALT, AST, TBIL, DBIL, IBIL, γ-GT and TBA in the infants with cholestasis were significantly higher compared to the healthy infants (P<0.01); the serum levels of CHE in the infants with cholestasis were significantly lower compared to the healthy infants (P<0.01). The serum levels of HA, PCIII, and cIV in the infants with cholestasis were significantly higher compared to the healthy infants (P<0.01). Correlation analyses between liver function and the four biomarkers of liver fibrosis showed that HA was positively correlated with AST and γ-GT (P<0.05) and negatively correlated with ALT, CHE and TBA (P<0.05). cIV was positively correlated with γ-GT (P<0.05) and negatively correlated with CHE (P<0.05). In conclusion, statistically significant differences were identified for the liver function markers (ALT, AST, TBIL, DBIL, IBIL, γ-GT and TBA) and the biomarkers HA, PCIII and cIV of liver fibrosis between infants with cholestasis and healthy infants. Thus, the serum levels of HA, cIV, γ-GT and CHE are sensitive markers for cholestatic liver fibrosis in infants. [ABSTRACT FROM AUTHOR]

Background: Stool colour assessment is a screening method for biliary tract obstruction in infants. This study is aimed to be a proof of concept work of digital photograph image analysis of stool colour compared to colour grading by a colour card, and the stool bilirubin level test.Materials and Methods: The total bilirubin (TB) level contents in stool samples from 17 infants aged less than 1 year, seven with confirmed cholestatic jaundice and ten healthy subjects was measured, and outcome correlated with the physical colour of the stool.Results: The seven infants with cholestasis included 6 cases of biliary atresia and 1 case of pancreatic mass. All pre-operative stool samples in these cases were indicated as grade 1 on the stool card (stool colour in healthy infants ranges from 4 to 6). The average stool TB in the pale stool group was 43.07 μg/g compared to 101.78 μg/g in the non-pale stool group. Of the 3 colour channels assessed in the digital photographs, the blue and green light were best able to discriminate accurately between the pre-operative stool samples from infants with cholestasis and the samples from the healthy controls. With red, green, and blue (RGB) image analysis using wave level as the ANN input, the system predicts the stool TB with a relationship coefficient of 0.96, compared to 0.61 when stool colour card grading was used.Conclusion: Input from digital camera images of stool had a higher predictive capability compared to the standard stool colour card, indicating using digital photographs may be a useful tool for detection of cholestasis in infants. [ABSTRACT FROM AUTHOR]

Background: Neonatal and infantile cholestasis can be associated with ocular findings that might aid in the diagnosis of diseases such as Alagille syndrome (AGS) and Niemann-Pick disease (NPD). Aim: We aimed to investigate the frequency of ocular manifestations in infants with cholestasis. Patients and methods: This cross-sectional study included cholestatic infants presenting to the Pediatric Hepatology Unit, Pediatric Hospital, Cairo University. All infants underwent ophthalmological examinations including anterior segment examination using a hand-held slit lamp, ocular motility, cycloplegic refraction, intraocular pressure measurement, and ocular ultrasonography. Results The study included 112 infants with various cholestatic disorders of infancy. Of them, 73 (65.2%) were male. The median age was 2 months. A diagnosis was reached in 39 cases: 14 had AGS, 14 had biliary atresia, four had NPD, four had posthemolytic cholestasis, two had cytomegalovirus neonatal hepatitis, and one case had hepatorenal tyrosinemia. Thirteen cases were probably having progressive familiar intrahepatic cholestasis types 1 or 2 in view of their persistent cholestasis in the presence of normal γ-glutamyl transpeptidase level. Sixty were left with a diagnosis of 'idiopathic neonatal hepatitis'. Ophthalmological assessment showed abnormal findings in 39 cases (34.8%). The most common finding was unilateral/bilateral optic nerve drusen in 12 cases (10.7%), followed by posterior embryotoxon in 11 (9.8%) cases. Ocular findings were observed in several cholestatic disorders, including in 64.3% of patients with AGS, 50% with NPD, 36.7% of infants with idiopathic neonatal hepatitis, and 14.3% with biliary atresia. Conclusion: Ophthalmological assessment should be part of the workup for the diagnosis and assessment of cholestatic infants. [ABSTRACT FROM AUTHOR]

Aim: Parenteral nutrition (PN) provides an alternative nutrition source for preterm infants who are intolerant of enteral nutrition. However, prolonged PN increases the risk of PN-associated cholestasis (PNAC). We conducted this study to determine the incidence and risk factors of PNAC in extremely low birth weight (ELBW) infants.Methods: We retrospectively reviewed the medical records of ELBW infants from March 2010 to April 2015. PNAC was diagnosed in infants with a history of PN for at least two weeks and direct bilirubin concentrations >2 mg/dL after other causes of neonatal cholestasis were excluded.Results: Of the 114 eligible ELBW infants, 41 (36%) were diagnosed with PNAC. The multivariate analysis showed that birth weight, sepsis, necrotising enterocolitis, fluconazole prophylaxis and the duration of PN and hospitalisation were independent risk factors for the development of PNAC (p < 0.05). However, parenteral fish oil-based lipid preparation (FOLP) did not reduce the risk of PNAC. Although PNAC was not a direct cause of death, it was associated with an increased risk of mortality.Conclusion: PNAC was common in ELBW infants, was associated with various clinical factors and increased the risk of mortality. However, we did not observe the protective effect of FOLP against PNAC. [ABSTRACT FROM AUTHOR]

Purpose The aim of this article is to differentiate neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) from biliary atresia (BA) by total hexose. Methods A total of 11 patients with NICCD, 29 patients with BA, and 4,898 children as controls were involved in this study. The blood concentration of amino acids, carnitine, acylcarnitines, and total hexose were measured in dry blood spots (DBS) using tandem mass spectrometry (MS/MS). Results In the patients with NICCD, the blood concentration of the total hexose (15.3 ± 9.0 mmol/L vs. 7.3 ± 2.7 mmol/L; p < 0.001), citrulline (Cit) (197.9 ± 93.7 µmol/L vs. 17.5 ± 7.4 µmol/L; p < 0.001) were higher than those of patients with BA. Using total hexose (> 10 mmol/L), Cit (> 55 µmol/L) to diagnose NICCD, the sensitivity and specificity were 66.7 and 97.8% and 90.0 and 99.1%, respectively, and all of the areas under the receiver-operating characteristic curves were greater than 0.85. Conclusion Elevated total hexose in DBS measured by MS/MS associated with elevated amino acids, especially Cit can be used to diagnose NICCD and differentiate it from BA. [ABSTRACT FROM AUTHOR]

Objective: To assess in a cohort of twin pregnancies the prevalence of obstetric cholestasis (OC) and its correlation with the type of conception and chorionicity.Methods: A retrospective cohort study including all the twin pregnancies delivered between 2005 and 2013 at our University Hospital was carried out. In the study population, the prevalence of OC was investigated in relationship to the impact of assisted reproductive technology (ART) and of chorionicity.Results: Overall, 569 twin pregnancies were included in the study population. Among those complicated by OC, the rate of ART was 3-fold higher (OR 3.4, 95% CI 1.2-9.5, p = 0.02), whereas the rate of dichorionicity did not differ significantly (OR 1.6, 95% CI 0.3-7.9, p = 0.53).Conclusion: The risk of developing OC seems to be significantly higher among twin pregnancies obtained after ART in comparison with those conceived spontaneously. [ABSTRACT FROM AUTHOR]