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Publications (219)
Background:
The immune heterogeneity of biliary atresia (BA) presents a challenge for development of prognostic biomarkers. This study aimed to identify early immune signatures associated with biliary drainage after Kasai Portoenterostomy (KPE).
Methods:
Serum samples, liver slides, and clinical data were obtained from patients enrolled in the N...
Background & Aims
High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort.
Approach & Results
MMP-7 was measured in serum samples of 399 cholestatic infants in th...
Background:
Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis a...
Background aims:
While a dysregulated type 1 immune response is integral to the pathogenesis of biliary atresia, studies in both humans and mice have uncovered a type 2 response, primarily driven by type 2 innate lymphoid cells. In non-hepatic tissues, natural ILC2s (nILC2s) regulate epithelial proliferation and tissue repair, whereas inflammatory...
Objective:
To evaluate whether the nature and severity of non-A-E severe acute hepatitis (NAESAH) in children noted by the WHO from late 2021 through early 2022 was indeed increased in 2021-2022 compared with prior years.
Study design:
We performed a single-center, retrospective study to track the etiology and outcomes of children with NAESAH in...
Background
Controversies in management of biliary atresia (BA) after hepatoportoenterostomy (HPE) lead to variable treatment protocols. We implemented standardized medical management after HPE, customizing the use of antibiotics and corticosteroids based on patient-specific factors.
Methods
In this retrospective analysis, 20 consecutive infants un...
Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC)...
Background & aims:
Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.
Approach & results:
A targeted ELISA-based panel of 9 biomarkers (lysyl oxidase (LOX), tissue inhibitor matrix metalloproteinase 1 (TIMP1),...
Background & aims:
In biliary atresia (BA), serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes...
The conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a publish...
Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn’s susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate admi...
Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large‐scale proteomics. We applied the slow off‐rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum sam...
Background & aims:
Biliary atresia is a severe inflammatory and fibrosing cholangiopathy of neonates of unknown etiology. The onset of cholestasis at birth implies a prenatal onset of liver dysfunction.
Aim:
To investigate the mechanisms linked to abnormal cholangiocyte development.
Approach & results:
We generated biliary organoids from liver...
Objectives:
To determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multi-center cohort of infants.
Methods:
We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they...
Liver disease in children is increasing in prevalence, placing a huge burden on healthcare systems and often requiring long-term management. Offering an integrative approach to the science and clinical practice of pediatric hepatology, this is the definitive reference text for improved diagnosis and treatment strategies. In the new edition of this...
Background and aims:
Biliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai hepatoportoenterostomy (HPE) restores biliary drainage in a subset of patients, but most patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. In the murine...
Approximately 50% of infants with biliary atresia (BA) undergoing Kasai portoenterostomy show survival with native liver (SNL) at age 2 years. Predictors of disease progression after age 2 years are unknown, despite estimates of 20%‐30% undergoing liver transplant (LT) between age 2 and 18 years. We sought to address this knowledge gap by developin...
Elastographic measurement of liver stiffness is of growing importance in the assessment of liver disease. Pediatric experiences with this technique are primarily single center and limited in scope. The Childhood Liver Disease Research Network provided a unique opportunity to assess elastography in a well‐characterized multi‐institutional cohort. Ch...
The etiology of portal hypertension (pHTN) in children differs from that of adults and may require different management strategies. We set out to review the etiology, management, and natural history of pHTN at a pediatric liver center. From 2008 to 2018, 151 children and adolescents with pHTN were identified at a free‐standing children’s hospital....
Extramedullary hematopoietic cells are present in the liver of normal neonates in the first few days of life and persist in infants with biliary atresia. Based on a previous report that liver genes are enriched by erythroid pathways, we examined the liver gene expression pattern at diagnosis and found the top five enriched pathways are related to e...
Background
Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical charact...
Objectives:
To assess neurodevelopmental outcomes among children with biliary atresia (BA) surviving with their native liver at age 3-12 years and evaluate variables that associate with neurodevelopment.
Methods:
Participants (age 3-12 years) in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with Weschler Pre...
Background & aims:
Little is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage.
Methods:
Liver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); messenger RNA (mRNA) was isolated,...
Objective:
To prospectively assess the diagnostic performance of ultrasound shear wave elastography (SWE) and hepatobiliary laboratory biomarkers for discriminating biliary atresia from other causes of neonatal cholestasis.
Study design:
Forty-one patients <3 months of age with neonatal cholestasis (direct bilirubin >2 mg/dL) and possible biliar...
IL-33 promotes type 2 immunity, epithelial repair, and tissue fibrosis by activating group 2 innate lymphoid cells (ILC2). ILC2 lack all known surface markers of mature T, B, NK, and myeloid cell lineages (Linneg), express the IL-33 receptor ST2, and release type 2 cytokines which contribute to cholangiocyte proliferation and activation of hepatic...
Single cell RNA sequencing reveals 17 unique cell classes of CD45+Linneg mononuclear cells in the liver and extrahepatic bile duct.
Cluster analysis of the top 200 genes identifies 17 total CD45+Linneg cell classes in the liver and/or EHBD in PBS- or IL-33 treated Balb/c mice. Gene expression is shown as a color gradient from yellow (high expressio...
BD-ILC1 associated proteins are not detected in hepatobiliary Linneg mononuclear cells.
Mice were treated with either PBS or IL-33 for 4 days, after which mononuclear cells were isolated from liver and EHBD as described in Methods, stained with fluorescent antibodies, and analyzed by flow cytometry. Cells were gated as shown in Fig 6 to identify CD...
CCR1, a BIM cell class associated protein, is not detected in hepatobiliary Linneg mononuclear cells.
Mice were treated with either PBS or IL-33 for 4 days, after which mononuclear cells were isolated from liver as described in Methods, stained with fluorescent antibodies, and analyzed by flow cytometry. Cells were gated as shown in Fig 7 to identi...
PBS and IL33 treated single cell gene expression matrix TPM value.
(ZIP)
Total cell yield of liver and EHBD mononuclear cells for single-cell RNA sequencing.
(DOCX)
PBS and IL33 treated whole Liver and BD gene expression matrix TPM value.
(ZIP)
Objectives:
Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administrat...
Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoent...
Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations —...
Objective:
To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with bilia...
The diagnosis of biliary atresia (BA) remains a clinical challenge because affected infants have signs, symptoms, and serum liver biochemistry that are also seen in those with other causes of neonatal cholestasis (non-BA). Yet, an early diagnosis and prompt surgical treatment are required to improve clinical outcome. Recently, the relative abundanc...
Background & aims:
Biliary atresia (BA) results from a neonatal inflammatory and fibrosing obstruction of bile ducts of unknown etiology. Although the innate immune system has been linked to virus-induced mechanism of disease, the role of the inflammasome-mediated epithelial injury remains largely undefined. Here, we hypothesized that disruption o...
Biliary atresia (BA) is a fibroinflammatory disease of the intra‐ and extrahepatic biliary tree. Without medical treatment, surgical hepatic portoenterosmy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further pro...
Objectives:
To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment.
Study design:
Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopm...
Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic sy...
We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that inc...
Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC], and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of p...
Biliary atresia is progressive fibro-inflammatory cholangiopathy of young children. Central to pathogenic mechanisms of injury is the tissue targeting by the innate and adaptive immune cells. Among these cells, neutrophils and the IL-8/Cxcl-8 signaling via its Cxcr2 receptor have been linked to bile duct injury. Here, we aimed to investigate whethe...
Pipeline workflow for 16S rRNA pre-processing step.
A LONI pipeline, composed of PANDAseq, QIIME and USEARCH was used for all 16S rRNA pre-processing step to obtain OTU tables.
(TIF)
Bacterial diversity in SMZ/TMP-treated WT and Cxcr2-/- mice receiving saline as controls.
(A) Microbial alpha diversity was measured by observed taxa and Chao1 for richness, and by Dominance and Shannon diversity index for evenness (n = 8–13 per group). SMZ/TMP exposure and/or mutation in Cxcr2 significantly increased bacterial diversity without af...
Oligonucleotide primers for 16s rRNA and Anaerococcus species.
Species detection by PCR used the combination of the following primers: #5 and 4 for A. hydrogenalis (amplicon size ~ 400 bp), #6 and 4 for A. lactolyticus (~ 150 bp), #7 and 4 for A. octavius (~ 760 bp), #8 and 4 for A. prevotii (~ 400 bp), #9 and 3 for A. tetradius (~ 150 bp), and #10...
Oligonucleotide primer sets (forward and reverse) used in real-time PCR for hepatic gene-expression analysis.
(DOCX)
Comparison of included (Group 1) and excluded (Group 3) infants with a clinical diagnosis of biliary atresia.
(DOCX)
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....
Institutional review boards.
(DOCX)
Comparison of included (Group 2) and excluded (Group 4) infants with a clinical diagnosis that was not biliary atresia.
(DOCX)
Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis. Although the pathogenesis of the disease is not completely understood, previous reports link TNFα to apoptosis of the bile duct epithelium in the presence of IFNγ. Here, we investigate if TNFα signaling regulates pathogenic mechanisms of biliary atre...
A self-organizing organoid model provides a new approach to study the mechanism of human liver organogenesis. Previous animal models documented that simultaneous paracrine signaling and cell-to-cell surface contact regulate hepatocyte differentiation. To dissect the relative contributions of the paracrine effects, we first established a liver organ...
Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in...
Objectives:
To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life.
Study design:
Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were...
Single-gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in about two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized...
Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses...
Unlabelled:
Biliary atresia is a rapidly progressive obstructive cholangiopathy of infants. Mechanistic studies in the mouse model of Rhesus rotavirus (RRV)-induced biliary atresia have linked the importance of effector lymphocytes to the pathogenesis of extrahepatic bile duct (EHBD) injury and obstruction in experimental biliary atresia; however,...
Unlabelled:
Cholangiocarcinoma (CCA) is a lethal hepatobiliary neoplasm originating from the biliary apparatus. In humans, CCA risk factors include hepatobiliary inflammation and fibrosis. The recently identified interleukin (IL)-1 family member, IL-33, has been shown to be a biliary mitogen which also promotes liver inflammation and fibrosis. Our...
Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia.
Infants enrolled in the Trial of Corticost...
Unlabelled:
Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased liver...
Injury to the biliary epithelium triggers inflammation and fibrosis, which can result in severe liver diseases and may progress to malignancy. Development of a type 1 immune response has been linked to biliary injury pathogenesis; however, a subset of patients with biliary atresia, the most common childhood cholangiopathy, exhibit increased levels...
The fourth edition of this authoritative text covers every aspect of liver disease affecting infants, children and adolescents. As in the previous editions, it offers an integrative approach to the science and clinical practice of pediatric hepatology and charts the substantial progress in understanding and treating these diseases. All of the chapt...
Unlabelled:
The etiology of biliary atresia (BA) is unknown. Given that patterns of anomalies might provide etiopathogenetic clues, we used data from the North American Childhood Liver Disease Research and Education Network to analyze patterns of anomalies in infants with BA. In all, 289 infants who were enrolled in the prospective database prior...
Biliary atresia is a fibroinflammatory obstruction of extrahepatic bile duct that leads to end-stage liver disease in children. Despite advances in understanding the pathogenesis of biliary atresia, very little is known about the role of microRNAs (miRNAs) in onset and progression of the disease. In this study, we aimed to investigate the entire bi...
In the United States, biliary atresia (BA) is the most frequent indication for liver transplantation in pediatric patients. BA is a complex disease, with suspected environmental and genetic risk factors. A genome-wide association study in Chinese patients identified association to the 10q24.2 (hg18) genomic region. This signal was upstream of two g...
Unlabelled:
Peribiliary glands (PBGs) are clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts (EHBDs). Though their function is largely undefined, they may represent a stem cell niche. Here, we hypothesized that PBGs are populated by mature and undifferentiated cells capable of proliferation in pathologic...
Biliary atresia represents obstructive cholangiopathy in infants progressing rapidly to cirrhosis and end-stage liver disease. Activated NK cells expressing Nkg2d have been linked to bile duct injury and obstruction by establishing contact with cholangiocytes. To define the mechanisms used by cytotoxic cells, we investigated the role of perforin an...
Cholestasis predisposes to fat-soluble vitamin (FSV) deficiencies. A liquid multiple FSV preparation made with tocopheryl polyethylene glycol-1000 succinate (TPGS) is frequently used in infants with biliary atresia (BA) because of ease of administration and presumed efficacy. In this prospective multicenter study, we assessed the prevalence of FSV...
To determine whether portoenterostomy (PE) revision in patients afflicted with biliary atresia (BA) is a viable treatment option and, if so, identify which patients may benefit.
BA, the most common cause of neonatal liver disease, results in biliary tract obstruction and hepatic fibrosis. Kasai PE is the initial surgical intervention performed and,...
Biliary atresia (BA) is a destructive cholangiopathy of childhood in which Th1 immunity has been mechanistically linked to the bile duct inflammation and obstruction that culminate in liver injury. Based on reports of decreased Th1 cytokines in some patients and the development of BA in mice lacking CD4+ T cells, we hypothesized that Th1-independen...
Biliary atresia is the most common cholangiopathy of childhood. During infancy, an idiopathic activation of the neonatal immune system targets the biliary epithelium, obstructs bile ducts, and disrupts the anatomic continuity between the liver and the intestine. Here, we use a model of virus-induced biliary atresia in newborn mice to trace the init...
Protein (a), globulin (b) and albumin (c) levels measured in blood from 10-week-old Lampe1 homozygote/heterozygote mutants or C57BL/6J mice. (n = 3 per group).
(TIF)
Targeting the Lampe1 critical region for exon enrichment using high-density long-oligo arrays. (a) Exons including 50 bp upstream/downstream sequence were defined based on the Mus musculus NCBI build 37.1 database (primary target region) and submitted for enrichment. The Nimblegen probe selection algorithm captured 98.7% of targeted sequence with 1...
Using a small scale ENU mutagenesis approach we identified a recessive germline mutant, designated Lampe1 that exhibited growth retardation and spontaneous hepatosteatosis. Low resolution mapping based on 20 intercrossed Lampe1 mice revealed linkage to a ∼14 Mb interval on the distal site of chromosome 11 containing a total of 285 genes. Exons and...
Biliary atresia is the most common cholangiopathy of childhood. With complete obstruction of segments or the entire length of extrahepatic bile ducts, the timely pursuit of hepatoportoenterostomy is the best strategy to restore bile drainage. However, even with prompt surgical intervention, ongoing injury of intrahepatic bile ducts and progressive...
aring for children brings many joys to the day of a pediatrician: sound nutritional guidance to foster growth, immunization to prevent infectious disease, timely use of antibiotics for an acute illness. But the encounter with an infant with jaundice and pale stools breaks a smooth day and heightens the fear of danger: does the infant have biliary a...
