Published Research

Total Records: 84; Page 1 of 1
TitleMediaAuthorsPublicationPublication Year Descending order
Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome
Berauer JP, Mezina AI, Okou DT, Sabo A, Muzny DM, Gibbs RA, Hegde MR, Chopra P, Cutler DJ, Perlmutter DH, Bull LN, Thompson RJ, Loomes KM, Spinner N, Rajagopalan R, Guthery SL, Moore B, Yandell M, Harpavat S, Magee JC, Kamath BM, Molleston JP, Bezerra JA, Murray KF, Alonso EM, Rosenthal P, Squires RH, Wang KS, Finegold MJ, Russo P, Sherker AH, Sokol RJ, Karpen SJ, ChiLDReN Hepatology2019
A Phase I/IIa Trial of Intravenous Immunoglobulin (IVIg) Therapy Following Portoenterostomy in Infants with Biliary Atresia.
Mack CL, Spino C, Alonso EM, Bezerra JA, Moore J, Goodhue C, Ng VL, Karpen SJ, Venkat VL, Loomes KM, Wang KS, Sherker AH, Magee JC, Sokol RJ, ChiLDReN Journal of Pediatric Gastroenterology and Nutrition2019
Impact of steroid therapy on early growth in infants with biliary atresia: The multi-center steroids in biliary atresia randomized trial
Alonso EM, Ye W, Hawthorne K, Venkat VL, Loomes KM, Mack CL, Hertel PM, Karpen SJ, Kerkar N, Molleston JP, Murray KF, Romero R, Rosenthal P, Schwarz K, Shneider BL, Suchy FJ, Turmelle YP, Wang K, Sherker AH, Sokol RJ, Bezerra JA, Magee JCJournal of Pediatrics2018
Bone density in children with chronic liver disease correlates with growth and cholestasis
Loomes KM, Spino C, Goodrich NP, Hangartner TN, Marker AE, Heubi J, Kamath BM, Shneider BL, Rosenthal P, Hertel PM, Karpen SJ, Molleston JP, Murray KF, Schwarz KB, Squires RH, Teckman JH, Turmelle YP, Alonso EM, Sherker AH, Magee JC, Sokol RJHepatology2018
A genome wide association study was performed to identify genes that could be related to biliary atresia susceptibility. The top gene candidate was EFEMP1, which encodes the protein fibulin-3, found in the extracellular matrix around bile ducts. EFEMP1 expression is increased in biliary atresia liver and also in other cholestatic liver disease samples compared to normal liver. The protein is expressed in blood vessels around the ducts in both normal and diseased liver, and expressed in bile ducts only in BA and other diseased liver samples. Further studies will be required to understand how EFEMP1 function might contribute to BA disease susceptibility.
Chen Y, Gilbert MA, Grochowski CM, McEldrew D, Llewellyn J, Waisbourd-Zinman O, Hakonarson H, Bailey-Wilson JE, Russo P, Wells RG, Loomes KM, Spinner N, Devoto MPLOS Genetics2018
Placebo-controlled randomized trial of an intestinal bile salt transport inhibitor for pruritus in alagille syndrome.
Shneider BL, Spino C, Kamath BM, Magee JC, Bass LM, Setchell KD, Miethke A, Molleston JP, Mack CL, Squires RH, Murray KF, Loomes KM, Rosenthal P, Karpen SJ, Leung DH, Guthery SL, Thomas DW, Sherker AH, Sokol RJHepatology Communications2018
We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.
Bove KE, Sheridan R, Fei L, Anders RA, Chung C, Cummings OW, Finegold MJ, Finn LS, Ranganathan S, Kim G, Lovell MA, Magid MS, Melin-Aldana H, Russo P, Shehata BM, Wang L, White FV, Chen Z, Spino C, Magee JCPediatric and Developmental Pathology2018
Neurodevelopmental outcome of young children with biliary atresia and native liver: Results from the ChiLDReN study.
Ng VL, Sorensen LG, Alonso EM, Fredericks EM, Ye W, Moore J, Karpen SJ, Shneider BL, Molleston JP, Bezerra JA, Murray KF, Loomes KM, Rosenthal P, Squires RH, Arnon R, Schwarz K, Turmelle YP, Haber BH, Sherker AH, Magee JC, Sokol RJJournal of Pediatrics2018
In murine sclerosing cholangitis, intrahepatic regulatory T cell (Treg) responses control hepatic CD8+ T cell proliferation which drive biliary injury and fibrosis. The authors show that IL-2c mediated intrahepatic Treg expansion improves phenotype and conclude that low-dose IL-2 treatment represents a promising new therapy for sclerosing cholangitis.
Taylor AE, Carey AN, Kudira R, Lages CS, Shi T, Lam S, Karns R, Simmons JR, Shanmukhappa K, Almanan M, Chougnet C, Miethke AHepatology2018
Objectives: Cirrhosis occurs in 5-10% of CF (cystic fibrosis) patients, often accompanied by portal hypertension. We analyzed three adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver death (LD), and risk factors for these in CF Foundation Patient Registry (CFFPR) subjects with reported cirrhosis.
Ye W, Narkewicz MR, Leung DH, Karnsakul W, Murray KF, Alonso EM, Magee JC, Schwarzenberg SJ, Weymann A, Molleston JP, CFLD-NET Journal of Pediatric Gastroenterology and Nutrition2018
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 syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker wasmatrixmetalloproteinase-7 (MMP-7),which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with g-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and an experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target.
Lertudomphonwanit C, Mourya R, Fei L, Zhang Y, Gutta S, Yang L, Bove KE, Shivakumar P, Bezerra JAScience Translational Medicine2017
Heterozygous mutations in the ABCB4 gene are associated with different chronic liver diseases in children and in mice (Abcb4). The authors report that reduced Abcb4 expression drives a pro-inflammatory hepatic phenotype and is associated with a disruption in phospholipid homeostasis in neonatal mice with extrahepatic biliary atresia (EHBA). In infants with EHBA, a predisposition to an inflammatory phenotype was also observed in concert with downregulated ABCB4 expression.
Carey AN, Zhang W, Setchell KD, Simmons JR, Shi T, Lages CS, Mullen M, Carroll K, Karns R, Bessho K, Sheridan R, Zhao X, Weber SN, Miethke APediatric Research2017
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.
Shneider BL, Moore J, Kerkar N, Magee JC, Ye W, Karpen SJ, Kamath BM, Molleston JP, Bezerra JA, Murray KF, Loomes KM, Whitington PF, Rosenthal P, Squires RH, Guthery SL, Arnon R, Schwarz KB, Turmelle YP, Sherker AH, Sokol RJPLOS ONE2017
We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although an elevated serum bilirubin was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation.
Russo P, Magee JC, Anders RA, Bove KE, Chung C, Cummings OW, Finegold MJ, Finn LS, Kim GE, Lovell MA, Magid MS, Melin-Aldana H, Rajagopalan S, Shehata BM, Wang L, White FV, Chen Z, Spino CAmerican Journal of Surgical Pathology2016
Biliary atresia (BA) is a progressive fibroinflammatory cholangiopathy affecting the bile ducts of neonates. Although BA is the leading indication for pediatric liver transplantation, the etiology remains elusive. Adducin 3 (ADD3) and X-prolyl aminopeptidase 1 (XPNPEP1) are 2 genes previously identified in genome-wide association studies as potential BA susceptibility genes. Using zebrafish, we investigated the importance of ADD3 and XPNPEP1 in functional studies.
Tang V, Cofer ZC, Cui S, Sapp V, Loomes KMJournal of Pediatric Gastroenterology and Nutrition2016
THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome
Tsai EA, Gilbert MA, Grochowski CM, Underkoffler LA, Meng H, Zhang X, Wang MM, Shitaye H, Hankenson KD, Piccoli DA, Lin H, Kamath BM, Devoto M, Spinner N, Loomes KMCellular and Molecular Gastroenterology and Hepatology2016
There is significant value in the early prediction of clinical outcomes after the Kasai hepatoportoenterstomy (HPE) for biliary atresia (BA). This study was designed based upon prior retrospective work from ChiLDReN (J. Pediatr. 2006;148:467-474). In these prospective investigations, a successful HPE was defined by the ability to achieve a total bilirubin less than 2 mg/dl in the first three months after HPE. Fifty percent (69/137) of infants did not have a successful HPE according to these criteria. These infants were at greater risk for subsequently developing ascites, low serum albumin levels and abnormal blood clotting studies. In addition, these infants were at 12-fold increased risk of requiring liver transplantation in the first two years of life and a 16-fold increased risk of dying or requiring liver transplantation in the first two years of life. We suggest that clinicians follow total bilirubin levels on a monthly basis for the first six months after HPE for BA. In those infants where total bilirubin does not drop below 2 mg/dl, careful attention should be paid to nutritional status, anticipatory guidance should be provided for the potential for development of progressive liver disease and consideration should be given to evaluation for liver transplantation.
Shneider BL, Magee JC, Karpen SJ, Rand EB, Narkewicz MR, Bass LM, Schwarz K, Whitington PF, Bezerra JA, Kerkar N, Haber B, Rosenthal P, Turnelle YP, Molleston JP, Murray KF, Ng VL, Wang KS, Romero R, Squires RH, Arnon R, Sherker AH, Moore J, Ye W, Sokol RJJournal of Pediatrics2016
Given that earlier diagnosis of biliary atresia predicts better outcome following surgery, screening of infants for biliary atresia has been considered by many. It has even been implemented in a number of countries, but not in the United States. This paper is collaborative report on the state of the art feasibility of screening newborns for biliary atresia in the US. This was put together as a collaborative effort between the American Academy of Pediatrics Committee on Fetus and Newborn and Section on Surgery and ChiLDReN.
Wang KS, Moss RL, Caty MG, Davidoff A, Fallat ME, Heiss KF, Holcomb G, Meyers RL, Thorne V, Watterberg KL, Aucott S, Benitz WE, Cummings JJ, Eichenwald EC, Goldsmith J, Poindexter BB, Puopolo K, Stewart DL, Barfield WD, Goldberg J, Lacaze T, Keels EL, Raju TN, Couto J, Kerkar N, Karpen SJ, Sokol RJ, Schwarz KB, Mogul DB, Harpavat SPediatrics2015
This multicenter, prospective study investigated the relationship between abdominal ultrasound findings and demographic, historical, and clinical features in children, 3-12 years, with cystic fibrosis (CF) through the North American Cystic Fibrosis Liver Disease Network (CFLD NET) to predict hepatic fibrosis. Unsuspected cirrhotic pattern was seen in 3.3% of young patients with CF, and heterogeneous pattern in 8.9%. Abnormal ultrasound and ursodeoxycholic acid use was associated with CF-related diabetes, and early P aeruginosa associated with normal ultrasound. Prospective assessment of these risk factors may identify potential interventional targets.
Leung DH, Ye W, Molleston JP, Weymann A, Ling S, Paranjape SM, Romero R, Schwarzenberg SJ, Palermo J, Alonso EM, Murray KF, Marshall BC, Sherker AH, Siegel MJ, Krishnamurthy R, Harned R, Karmazyn B, Magee JC, Narkewicz MR, CFLD-NET Journal of Pediatrics2015
This is an analysis of quality of life in children and their parents with Alagille syndrome, in comparison to children with other chronic liver diseases. Children with Alagille syndrome clearly have reduced quality of life. Growth failure appears to be the major determinant of impaired quality of life in Alagille syndrome. This is significant because poor growth is a potentially treatable cause of poor quality of life.
Kamath BM, Chen Z, Romero R, Fredericks EM, Alonso EM, Arnon R, Hertel PM, Karpen SJ, Loomes KM, Murray KF, Rosenthal P, Schwarz KB, Subbarao G, Teckman JH, Turmelle YP, Wang KS, Sherker AH, Sokol RJ, Magee JC, ChiLDReN Journal of Pediatrics2015
Induced pluripotent stem cells (iPSCs) are stem cells that are derived from mature cells (a skin sample or blood). iPSCs can be made to develop into many different cell types in order to study disease. In this study, we describe a method to differentiate bile duct cells (cholangiocytes) from iPSCs. We demonstrate how this technology can be used to study cystic fibrosis liver disease. This platform will be useful to study many other biliary diseases.
Ogawa M, Ogawa S, Bear CE, Ahmadi S, Chin S, Li B, Grompe M, Keller G, Kamath BM, Ghanekar ANature Biotechnology2015
Mitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial DNA or POLG are often present, other nuclear defects in mitochondrial DNA replication and protein translation have been associated with a severe epileptic encephalopathy.
Coughlin 2nd CR, Scharer GH, Friederich MW, Yu HC, Geiger EA, Creadon-Swindell G, Collins AE, Vanlander AV, Coster RV, Powell CA, Swanson MA, Minczuk M, Van Hove JL, Shaikh THJournal of Medical Genetics2015
This is the first report of the patients with alpha-1-antitrypsin deficiency enrolled in the LOGIC study of the ChiLDREN Network. Enrollment began in 2008 and includes patients with both mild and severe liver disease, as well as a group who have already received liver transplants. The results show that in most cases the growth and development of all the children are normal, regardless of the severity of their disease. The quality of life is also generally high. Studies of the routine medical care of these patients indicates that detailed follow up is needed to appropriately identify and to treat the most severe patients, as many routine liver blood tests do not effectively differentiate the mild from the severe liver disease patients. Enrollment into this study will continue and further analysis of the data will continue.
Teckman JH, Rosenthal P, Abel R, Bass LM, Michail S, Murray KF, Rudnick DA, Thomas DW, Spino C, Arnon R, Hertel PM, Heubi J, Kamath BM, Karnsakul W, Loomes KM, Magee JC, Molleston JP, Romero R, Shneider BL, Sherker AH, Sokol RJ, ChiLDReN Journal of Pediatric Gastroenterology and Nutrition2015
Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal mucroarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband.
Tsai EA, Grochowski CM, Falsey AM, Rajagopalan R, Wendel D, Devoto M, Krantz ID, Loomes KM, Spinner NHuman Mutation2015
We used a biliary secretion assay in zebrafish to isolate a previously undescribed isoflavonoid, biliatresone, from Dysphania species implicated in a recent BA outbreak. This compound caused selective destruction of the extrahepatic, but not intrahepatic, biliary system of larval zebrafish. A mutation that enhanced biliatresone toxicity mapped to a region of the zebrafish genome that has conserved synteny with an established human BA susceptibility locus. The toxin also caused loss of cilia in neonatal mouse extrahepatic cholangiocytes in culture and disrupted cell polarity and monolayer integrity in cholangiocyte spheroids. Together, these findings provide direct evidence that BA could be initiated by perinatal exposure to an environmental toxin.
Lorent K, Gong W, Koo KA, Waisbourd-Zinman O, Karjoo S, Zhao X, Sealy I, Kettleborough RN, Stemple DL, Windsor PA, Whittaker SJ, Porter JR, Wells RG, Pack MScience Translational Medicine2015
δ-Bilirubin (Bδ) forms when bilirubin conjugates covalently bind to albumin by way of nonenzymatic transesterification in patients with cholestasis. Infants with cholestasis with biliary atresia form Bδ. The aim of the present study was to investigate the factors determining serum Bδ concentrations in infants with biliary atresia.
Ye W, Rosenthal P, Magee JC, Whitington PF, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2015
The investigators analyzed the genes in livers of children with biliary atresia to determine if they differ from other types of pediatric liver disease. They found the livers in biliary atresia have greater level of activation of inflammation genes. Among these genes, interleukin-8 (IL-8) was particularly interesting because it was increased in biliary atresia as well as in a mouse model of experimental biliary atresia. In this mouse, the inactivation of IL-8 decreased inflammation and obstruction of bile ducts, and improved long-term survival. These findings suggest that liver gene studies may aid in diagnosis of disease, and that IL-8 pathways may be treatment targets in future studies.
Heubi J, Setchell KD, Jha P, Buckley D, Zhang W, Rosenthal P, Potter C, Horslen S, Suskind DHepatology2015
Fat soluble vitamin (FSV) deficiency is a consequence of cholestatic liver disease. A reliable biomarker could provide a method of screening for patients who should be aggressively monitored for FSV deficiency. We studied infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia (START) after hepatoportoenterostomy receiving standardized FSV supplementation and monitoring of total bilirubin (TB), serum bile acids (SBA) and FSV levels. Our findings suggest that serum TB in infants with biliary atresia is a robust biomarker of FSV insufficiency and that it is superior to SBA.
Venkat VL, Shneider BL, Magee JC, Turmelle YP, Arnon R, Bezerra JA, Hertel PM, Karpen SJ, Kerkar N, Loomes KM, Molleston JP, Murray KF, Ng VL, Raghunathan T, Rosenthal P, Schwarz K, Sherker AH, Sokol RJ, Teckman JH, Wang K, Whitington PF, Heubi J, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2014
To examine the medical status of children with biliary atresia (BA) with their native livers after hepato- portoenterostomy (HPE) surgery.
Ng VL, Haber BH, Magee JC, Miethke A, Murray KF, Michail S, Karpen SJ, Kerkar N, Molleston JP, Romero R, Rosenthal P, Schwarz KB, Shneider BL, Turmelle YP, Alonso EM, Sherker AH, Sokol RJ, Childhood Liver Disease Research and Education Net Journal of Pediatrics2014
The investigators analyzed the genes in livers of children with biliary atresia to determine if they differ from other types of pediatric liver disease. They found the livers in biliary atresia have greater level of activation of inflammation genes. Among these genes, interleukin-8 (IL-8) was particularly interesting because it was increased in biliary atresia as well as in a mouse model of experimental biliary atresia. In this mouse, the inactivation of IL-8 decreased inflammation and obstruction of bile ducts, and improved long-term survival. These findings suggest that liver gene studies may aid in diagnosis of disease, and that IL-8 pathways may be treatment targets in future studies.
Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Rao M, Jegga AG, Bezerra JAHepatology2014
The investigators carried out a clinical trial to determine whether the use of high dose corticosteroids after the Kasai surgery improves biliary drainage and survival with the native liver. The trial was called Steroids in Biliary Atresia Randomized Trial (START) and was conducted in 140 infants with an average age of 2.3 months in several centers of the Network. The trial design included high doses of methylprednisolone/oral prednisolone or placebo initiated within 72 hours of surgery. They found that corticosteroids did not improve bile drainage at 6 months after surgery or transplant-free survival when compared to the placebo group at 24 months of age. They also found that participants receiving steroids had earlier time of onset of their first serious adverse when compared to placebo. They concluded that high dose steroid therapy following the steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia.
Bezerra JA, Spino C, Magee JC, Shneider BL, Rosenthal P, Wang KS, Erlichman J, Haber B, Hertel PM, Karpen SJ, Kerkar N, Loomes KM, Molleston JP, Murray KF, Romero R, Schwarz KB, Shepherd R, Suchy FJ, Turmelle YP, Whitington PF, Moore J, Sherker AH, Robuck P, Sokol RJ, Childhood Liver Disease Research and Education Net Journal of the American Medical Association2014
Mutations in TJP2 cause progressive cholestatic liver disease
Sambrotta M, Strautnieks SS, Papouli E, Rushton P, Clark BE, Parry DA, Logan CV, Newbury LJ, Kamath BM, Ling S, Grammatikopoulos T, Wagner BE, Magee JC, Sokol RJ, Mieli-Vergani G, University of Washington Center for Mendelian Geno , Smith JD, Johnson CA, McClean P, Simpson MA, Knisely AS, Bull LN, Thompson RJNature Genetics2014
In the study by Tsai et al. 2013, we carried out a Genome-Wide Association Study (GWAS) in 171 Caucasian patients with biliary atresia and 1,630 control individuals. We focused on a region of chromosome 10 that had previously been implicated as a possible disease locus for biliary after a GWAS study in a Chinese population. We were able to further fine-map the previously identified signal that had been near the XPNPEP1 and ADD3 genes, localizing it within an intron of the ADD3 gene.
Tsai EA, Grochowski CM, Loomes KM, Bessho K, Hakonarson H, Bezerra JA, Russo P, Haber BA, Spinner N, Devoto MHuman Genetics2014
This paper describes a study testing whether it was feasible to use remote electronic monitoring for verification of data from clinical trials, instead of in-person monitoring, which is one of the major costs of doing clinical trials. Data from the START (Steroids in Biliary Atresia Trial) as well as other clinical trials in adults were used to compare remote monitoring to in-person monitoring. The study showed that more than 99% of data could be monitored remotely and that this was a feasible way to reduce costs of monitoring during clinical trials.
Mealer M, Kittelson J, Thompson BT, Wheeler AP, Magee JC, Sokol RJ, Moss M, Kahn MGPLOS ONE2013
In all, 289 infants who were enrolled in the prospective database prior to surgery at any of 15 participating centers were evaluated for major birth defects. Eighty-four percent of the total (242/289) infants) had no major defects. Ten percent of the infants (30/289) had what used to be called “fetal embryonal” syndromic defects or laterality defects with a classical pattern of abnormalities known to be associated with each other: malformation or absence of the spleen, switching of the organs from one side of the body to the other (“situs inversus”) and certain heart defects known to be associated. The new information in this report was that six percent of the infants (17/289) had multiple malformations not classically considered laterality defects: cardiovascular (71%), gastrointestinal (24%) and genitourinary anomalies (47%). These three groups of infants suggest that BA may have multiple causes.
Mack CL, Anderson KM, Aubrey MT, Rosenthal P, Sokol RJ, Freed BMSpringerPlus2013
In all, 289 infants who were enrolled in the prospective database prior to surgery at any of 15 participating centers were evaluated for major birth defects. Eighty-four percent of the total (242/289) infants) had no major defects. Ten percent of the infants (30/289) had what used to be called “fetal embryonal” syndromic defects or laterality defects with a classical pattern of abnormalities known to be associated with each other: malformation or absence of the spleen, switching of the organs from one side of the body to the other (“situs inversus”) and certain heart defects known to be associated. The new information in this report was that six percent of the infants (17/289) had multiple malformations not classically considered laterality defects: cardiovascular (71%), gastrointestinal (24%) and genitourinary anomalies (47%). These three groups of infants suggest that BA may have multiple causes.
Schwarz KB, Haber BH, Rosenthal P, Mack CL, Moore J, Bove KE, Bezerra JA, Karpen SJ, Kerkar N, Shneider BL, Turmelle YP, Whitington PF, Molleston JP, Murray KF, Ng VL, Romero R, Wang KS, Sokol RJ, Childhood Liver Disease Research and Education Net Hepatology2013
Health related quality of life (HRQOL) looks at physical, psychological (including emotional and cognitive), and social health and is important in understanding the effect of a chronic disease on children and their families. In this study from the ChiLDReN network, we measured HRQOL in 221 children with biliary atresia (BA) who had not undergone liver transplant and in 151 following liver transplant. HRQOL in emotional and psychosocial functioning were poorer in the BA children than healthy children. There were no HRQOL differences in BA patients who had undergone liver transplant compared to those who had not had a liver transplant. An elevated serum bilirubin level and black race were associated with lower HRQOL in BA. This study identified important opportunities to improve overall health of children with biliary atresia.
Sundaram SS, Alonso EM, Haber B, Magee JC, Fredericks EM, Kamath BM, Kerkar N, Rosenthal P, Shepherd R, Limbers C, Varni JW, Robuck P, Sokol RJ, Childhood Liver Disease Research and Education Net Journal of Pediatrics2013
This paper outlines a tiered approach to the evaluation of the child with suspected mitochondrial liver disease. A detailed table summarizes clinical presentations and underling gene defects in recognized mitochondrial hepatopathies.
Molleston JP, Sokol RJ, Karnsakul W, Miethke A, Horslen S, Magee JC, Romero R, Squires RH, Van Hove JL, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2013
In this manuscript, the authors report their findings of abnormal extrahepatic cholangiocyte cilia in both human biliary atresia and in the rhesus rotavirus mouse model. These results suggest that the abnormalities of bile duct cilia may be part of the pathophysiology of biliary atresia.
Karjoo S, Hand NJ, Loarca L, Russo P, Friedman JRJournal of Pediatric Gastroenterology and Nutrition2013
Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gen
Cui S, Leyva-Vega M, Tsai EA, EauClaire SF, Glessner JT, Hakonarson H, Devoto M, Haber BA, Spinner N, Matthews RPGastroenterology2013
The final step in bile acid synthesis involves conjugation with glycine and taurine, which serves to promote fat and fat soluble vitamin absorption. We described the clinical, biochemical, molecular and liver biopsy features of a genetic defect in bile acid conjugation in 10 infants/children who presented with fat-soluble vitamin deficiency, often growth failure, and in some, transient neonatal cholestatic liver disease. Urinary bile acids were elevated and predominantly unconjugated. Glycine or taurine conjugates were absent in the urine, bile and serum. Unconjugated bile acids accounted for all but 4% of the bile acids in duodenal bile with concentrations too low for efficient fat and fast soluble vitamin absorption. The biochemical profile was consistent with a defect in bile acid conjugation with 4 different homozygous mutations in 8 patients tested. These findings suggest that patients with neonatal cholestasis of unknown cause and later onset unexplained fat-soluble vitamin deficiency should be screened for defects in bile acid conjugation
Setchell KD, Heubi J, Shah S, Lavine JE, Suskind D, Al-Edreesi M, Potter C, Russell DW, OConnell NC, Wolfe B, Jha P, Zhang W, Bove KE, Knisely AS, Hofmann AF, Rosenthal P, Bull LNGastroenterology2013
This review details the plausible role of virus infection, autoimmunity and a dysregulated immune response in the pathogenesis of biliary atresia.
Mack CL, Feldman AG, Sokol RJSeminars in Liver Disease2012
Alagille syndrome affects many different parts of the body in addition to the liver. Older research suggested that the pancreas can be affected in Alagille syndrome. The pancreas is an organ near the liver and intestine that has several functions, including producing enzymes which travel to the intestine where they are essential for breaking down fat in the diet. We wanted to evaluate this enzyme function of the pancreas in patients with Alagille syndrome. We tested the stools of 42 children with Alagille syndrome for a pancreatic enzyme known as fecal elastase. This is a very good test of pancreatic function. In our study none of the patients had an abnormal fecal elastase measurement. This indicates that pancreatic problems are not a significant problem in Alagille syndrome and testing of the pancreas should not be performed routinely.
Kamath BM, Piccoli DA, Magee JC, Sokol RJ, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2012
Biliary atresia in most circumstances leads to scarring of the liver that may progress to a severe form of scarring referred to as cirrhosis. In the setting of cirrhosis, blood from the intestines and spleen cannot flow through the liver normally and pressure builds up in the blood vessels leading into the liver. This build up of pressure is called portal hypertension. The pressure in these blood vessels is not typically measured directly and therefore clinical findings are used as markers of portal hypertension. Portal hypertension can lead to serious medical problems including bleeding into the intestines, accumulation of fluid in the abdomen, low oxygen levels in blood and build up of toxins. This study looked at portal hypertension in 163 children with biliary atresia who had not had a liver transplant and who were being cared for at centers involved in the Childhood Liver Disease Research and Education Network. The average age of children in this study was 9 years. Portal hypertension was present in about two thirds of the children. Growth was near normal in the children with biliary atresia both with and without portal hypertension. Blood tests were looked at to determine how well the liver functioned. In general liver function was slightly below normal in these children whether they had portal hypertension or not. As would be expected, white blood cell and platelet counts were lower in children with portal hypertension. Overall, children with biliary atresia often have evidence of portal hypertension but are growing well and have a mild reduction in liver function. These children are continuing to be followed by the Childhood Liver Disease Research and Education Network. Future reports will tell us if and when portal hypertension leads to problems for these children.
Shneider BL, Abel B, Haber B, Karpen SJ, Magee JC, Romero R, Schwarz KB, Bass LM, Kerkar N, Miethke A, Rosenthal P, Turmelle YP, Robuck P, Sokol RJ, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2012
The lack of reliable noninvasive diagnostic biomarkers of biliary atresia (BA) results in delayed diagnosis and worsened patient outcome. We examined the ability of serum miRNAs to distinguish BA from other forms of neonatal hyperbilirubinemia. We found that circulating levels of the miR-200b/429 cluster are elevated in infants with BA and have promising diagnostic clinical performance.
Zahm AM, Hand NJ, Boateng LA, Friedman JRJournal of Pediatric Gastroenterology and Nutrition2012
Intestinal absorption of fat-soluble vitamins (e.g. vitamins A, D, E and K) is dependent upon the presence of bile acids in the intestine. Infants with biliary atresia may be at risk for fat-soluble vitamin insufficiency due to a potential reduction in bile that is secreted from the liver into the intestine. A multivitamin preparation (ADEKs® or AquADEKs®) that contains a form of vitamin E that is absorbed independent of bile acids is used as a supplement in infants with biliary atresia because it has been presumed to be efficacious. The ChiLDREN consortium prospectively assessed the efficacy of this multivitamin preparation in infants with biliary atresia. Infants with biliary atresia whose total bilirubin was greater than 2 mg/dl in the first 6 months after a Kasai procedure were at high risk of having at least one vitamin insufficiency (either vitamin A, D or E) when standard doses of this multivitamin preparation were utilized. Individual fat-soluble vitamin supplementation and monitoring is necessary to provide optimal fat-soluble vitamin blood levels in infants with biliary atresia who have a total bilirubin greater than 2 mg/dL.
Shneider BL, Magee JC, Bezerra JA, Haber B, Karpen SJ, Raghunathan T, Rosenthal P, Schwarz KB, Suchy FJ, Kerkar N, Turmelle YP, Whitington PF, Robuck P, Sokol RJ, Childhood Liver Disease Research and Education Net Pediatrics2012
In Notch Signaling in Human Development and Disease, Penton et al. review the evidence for involvement of mutations in NOTCH signaling pathway genes in human developmental disease. The review the evidence for mutations in Notch pathway ligands JAG1 (Alagille syndrome and cardiac disease), Delta-like 3 (spondylocostal dysostosis); and Notch receptors NOTCH1 (cardiac disease) and NOTCH2 (Alagille syndrome and Hajdu Cheney Syndrome. Other Notch signaling pathway members HES7, lunatic fringe, and MESP2 have also been associated with vertebral defects seen in spondylocostal dysostosis.
Penton AL, Leonard L, Spinner NSeminars in Cell & Developmental Biology2012
Isolated cases of syndromic biliary atresia have been shown to result from abnormalities in proteins associated with motile cilia. Cholangiocytes have primary cilia, which are solitary, non-motile cilia. In this study, liver tissue samples from patients with syndromic or non-syndromic biliary atresia, or with unrelated liver diseases, were stained to examine the number and morphology of the primary cilia on cholangiocytes. Compared to livers not affected by biliary atresia, livers with either form of biliary atresia demonstrated cholangiocytes with significantly decreased numbers of primary cilia, and those cilia present were morphologically abnormal. This suggests that cellular changes resulting in abnormal cilia could be a common mechanism in syndromic and non-syndromic biliary atresia.
Chu AS, Russo P, Wells RGModern Pathology2012
This letter to the editor describes a liver explant with multiple small, well-differentiated dysplastic nodules in a previously reported older patient with progressive relatively indolent cholestatic liver disease, who is a compound heterozygote for ABCB11 mutation. This extends previous observations in clinically more severe BSEP deficiency and supports the proposition that risk for HCC in ABCB11 disease is elevated in association with functional BSEP deficiency as well as with complete loss of BSEP expression.
Sheridan RM, Gupta A, Miethke A, Knisely AS, Bove KEAmerican Journal of Surgical Pathology2012
Liver T-cell responses to CMV were identified in the majority of BA patients at diagnosis, suggesting perinatal CMV infection as a plausible initiator of bile duct damage. Deficiency of Tregs in BA patients implies decreased inhibition of inflammation and autoreactivity, leading to exaggerated bile duct injury.
Brindley SM, Lanham AM, Karrer FM, Tucker RM, Fontenot AP, Mack CLHepatology2012
NOTCH2 mutations in Alagille syndrome
Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, Lapunzina P, Leonard L, Ling S, Ng VL, Hoang PL, Piccoli DA, Spinner NJournal of Medical Genetics2012
Using a mouse model of experimental atresia, the investigators found that the type-2 cytokine interleukin-13 (IL-13) played a key role in pathogenesis of bile duct injury. Quantifying this cytokine in serum of children at the time of diagnosis of biliary atresia, IL-13 and other type-2 cytokines increased in a subset of children. This is the first study to show a link between type-2 cytokines in biliary atresia.
Li J, Bessho K, Shivakumar P, Mourya R, Mohanty SK, Dos Santos JL, Miura IK, Porta G, Bezerra JAThe Journal of Clinical Investigation2011
The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival
Superina R, Magee JC, Brandt ML, Healey PJ, Tiao G, Ryckman F, Karrer FM, Iyer K, Fecteau A, West K, Burns RC, Flake A, Lee H, Lowell JA, Dillon P, Colombani P, Ricketts R, Li Y, Moore J, Wang KS, Childhood Liver Disease Research and Education Net Annals of Surgery2011
The investigators studied the number and function of dendritic cells in the livers of mice and children with biliary atresia. They found increase in the number of activated dendritic cells, and the removal of the cells prevented the disease in mice. These findings identified dendritic cells as key cellular triggers of biliary injury.
Saxena V, Shivakumar P, Sabla G, Mourya R, Chougnet C, Bezerra JAScience Translational Medicine2011
This study examined the function of a specific set of cells in the liver, cells expressing the transcription factor Foxl1. Foxl1 is thought to be a progenitor cell marker, and this study showed that Foxl1-expressing cells could differentiate into both hepatocytes and cholangiocytes, depending on the culture conditions, consistent with their being progenitor cells.
Shin S, Walton G, Aoki R, Brondell K, Schug J, Fox A, Smirnova O, Dorrell C, Erker L, Chu AS, Wells RG, Grompe M, Greenbaum LE, Kaestner KHGenes & Development2011
Twelve children with PFIC2 had light and electron microscopy of liver biopsies as well as genetic evaluation of the BSEP gene, ABCB11.The age at presentation, pace of progressive liver disease and specific genetic mutations were highly varied. Indolent course was noted in two patients with mutations who had demonstrable BSEP in liver canaliculi. Possible linkage was observed between mutations that ended BSEP transcription and severity of hepatocellular injury (necrosis and fibrosis). However, no definitive correlation between specific mutations and histopathology was established in this small series of well-studied patients.
Evason K, Bove KE, Finegold MJ, Knisely AS, Rhee S, Rosenthal P, Miethke A, Karpen SJ, Ferrell LD, Kim GEAmerican Journal of Surgical Pathology2011
Some investigators believe that epithelial cells such as cholangiocytes and hepatocytes in the injured liver undergo an epithelial-to-mesenchymal transition (EMT), such that they lose their epithelial identity and become myofibroblasts, a form of mesenchymal cell that can secrete collagens and other matrix proteins making up scar tissue (fibrosis). In this study, all cholangiocytes and hepatocytes were genetically modified so that they and cells derived from them could be traced. When the livers from mice with these labeled cells were injured, there was no evidence that any of the cells involved in making scar tissue were derived from epithelial cells. In combination with two studies from another group, this strongly suggested that, at least in mouse models, EMT is not an important process in the generation of fibrosis.
Chu AS, Diaz R, Hui JJ, Yanger K, Zong Y, Alpini G, Stanger BZ, Wells RGHepatology2011
The BARC histological assessment system (for studying liver biopsies) identified features of liver biopsies from jaundiced infants, with good agreement between liver pathologists who read the biopsies that might be used in diagnosis and determination of future medical course. The system diagnosed biliary atresia (BA) quite well and identified infants with biliary obstruction with reasonable agreement between pathologists. However, distinguishing between BA and disorders such as total parenteral nutrition associated liver disease and alpha-1-antitrypsin deficiency is not possible without adequate clinical information.
Russo P, Magee JC, Boitnott J, Bove KE, Raghunathan T, Finegold MJ, Haas J, Jaffe R, Kim GE, Magid MS, Melin-Aldana H, White FV, Whitington PF, Sokol RJ, Biliary Atresia Research Consortium Clinical Gastroenterology and Hepatology2011
Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of beta-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. However, the role of long-chain fatty acid oxidation in the brain and other tissues that do not rely on fat for energy is poorly understood. Here we characterize two new ACADs, ACAD10 and ACAD11, both with significant expression in human brain.
He M, Pei Z, Mohsen AW, Watkins PA, Murdoch G, Van Veldhoven PP, Ensenauer R, Vockley JMolecular Genetics and Metabolism2011
The investigators analyzed the genes in livers of children with biliary atresia to determine if they differ from other types of pediatric liver disease. They found the livers in biliary atresia have greater level of activation of inflammation genes. Among these genes, interleukin-8 (IL-8) was particularly interesting because it was increased in biliary atresia as well as in a mouse model of experimental biliary atresia. In this mouse, the inactivation of IL-8 decreased inflammation and obstruction of bile ducts, and improved long-term survival. These findings suggest that liver gene studies may aid in diagnosis of disease, and that IL-8 pathways may be treatment targets in future studies.
Bessho K, Bezerra JAAnnual Review of Medicine2011
The investigators screened for genetic mutations in the genes SERPINA1A, ATP8B1, ABCB11, ABCB4 and JAG1 in 51 children with chronic intrahepatic cholestasis of undefined etiology. Sequence analysis assigned a molecular diagnosis in 27% of the patients based on the presence of variants likely to cause disease phenotypes.
Matte U, Mourya R, Miethke A, Liu C, Kauffmann G, Moyer K, Zhang K, Bezerra JAJournal of Pediatric Gastroenterology and Nutrition2010
Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy
Van Hove JL, Saenz MS, Thomas JA, Gallagher RC, Lovell MA, Fenton LZ, Shanske S, Myers SM, Wanders RJ, Ruiter J, Turkenburg M, Waterham HRPediatric Research2010
Differences in presentation and progression between severe FIC1 and BSEP deficiencies
Pawlikowska L, Strautnieks SS, Jankowska I, Czubkowski P, Emerick K, Antoniou A, Wanty C, Fischler B, Jacquemin E, Wali SH, Blanchard S, Nielsen IM, Bourke B, McQuaid S, Lacaille F, Bryne JA, van Eerde AM, Kolho KL, Klomp L, Houwen R, Bacchetti P, Lobritto S, Hupertz V, McClean P, Mieli-Vergani G, Shneider BL, Nemeth A, Sokal E, Freimer NB, Knisely AS, Rosenthal P, Whitington PF, Pawlowska J, Thompson RJ, Bull LNJournal of Hepatology2010
The investigators analyzed the human genome to determine whether the expression of gene groups can provide insight into the stages of liver disease at the time of diagnosis. To this end, they scored the degree of inflammation and fibrosis (scarring) in the liver biopsies from 47 infants with biliary atresia. They also quantified the expression of all human genes in the liver biopsies using a gene chip. The investigators found that about 1/3 of the patients had either inflammation or fibrosis in the livers at the time of diagnosis using standard anatomical criteria. In contrast, using a new method to classify the patients based on the pattern of gene expression (also known as molecular profiling), they were able to stage the disease into inflammation or fibrosis in a greater percentage of the patients and to link fibrosis with poor outcome. The implication of the findings is that the liver disease of babies with biliary atresia has variable degrees at diagnosis. Future studies will examine whether the use of molecular profiling will aid the monitoring of patients and the design of clinical trials.
Moyer K, Kaimal V, Pacheco C, Mourya R, Xu H, Shivakumar P, Chakraborty R, Rao M, Magee JC, Bove KE, Aronow BJ, Jegga AG, Bezerra JAGenome Medicine2010
Leyva-Vega et al. screened a cohort of 35 patients with biliary atresia using a genome-wide SNP based chromosomal microarray (CMA) analysis test to look for deletions and duplications that might be associated with the disorder. They identified two patients with large, overlapping deletions on chromosome 2, suggesting that there might be a BA susceptibility locus in this region of the chromosome. There was a 1.76 Mb overlapping regions at the intersection of the 2 deletions, that contained 30 genes, that can be considered BA candidate genes.
Leyva-Vega M, Gerfen J, Thiel BD, Jurkiewicz D, Rand EB, Pawlowska J, Kaminska D, Russo P, Gai X, Krantz ID, Kamath BM, Hakonarson H, Haber BA, Spinner NAmerican Journal of Medical Genetics2010
Biliary atresia (BA) is the most serious liver disease in infants. Diagnosis currently depends on surgical exploration of the biliary tree. Noninvasive tests that distinguish BA from other types of neonatal liver disease are not available.
Wang H, Malone JP, Gilmore PE, Davis AE, Magee JC, Townsend RR, Heuckeroth ROJournal of Pediatric Gastroenterology and Nutrition2010
A discussion of bile acid synthesis defects and their challenges as an example of a rare cholestatic childhood liver disease is presented. An argument is provided supporting the benefits of collaboration among centers, countries and continents in unraveling the causes, modifying factors and the conduct of clinical trials in rare liver diseases. The challenges ahead will be to obtain sustainable resources and funding, to develop robust national and international registries and annotated tissue/DNA repositories for rare diseases, to capitalize on the implementation of electronic medical records, and to formulate and disseminate best practices to practitioners.
Sokol RJJournal of Pediatric Gastroenterology and Nutrition2010
The acyl-CoA dehydrogenases (ACADs) are enzymes that catalyze the alpha,beta-dehydrogenation of acyl-CoA esters in fatty acid and amino acid catabolism. Eleven ACADs are now recognized in the sequenced human genome. We performed a systematic comparative genomic study, integrating homology searches with methods of phylogenetic reconstruction, to investigate the evolutionary history of this family. Our finding that eukaryotic ACAD species are more closely related to bacterial ACADs is consistent with endosymbiotic origin of ACADs in eukaryotes and further supported by the localization of all nine previously studied ACADs in mitochondria.
Swigonova Z, Mohsen AW, Vockley JJournal of Molecular Evolution2009
This commentary describes various approaches to screening infants for biliary atresia, the potential advantages of these approaches, and the need for a newborn screening test that would be appropriate for North America
Sokol RJPediatrics2009
Over 7000 rare diseases affect nearly 30 million people in the United States. Furthermore, for the 10% of people with a rare disease and for their families, these disorders no longer seem rare. Molecular genetics have characterized the cause of many rare diseases and provide unprecedented opportunities for identifying patients, determining phenotypes, and devising treatments to prevent, stabilize, or improve each disease. The U.S. Orphan Drug Act of the U.S. FDA has stimulated industry investment in clinical trials to develop treatments for rare diseases. For trainees interested in finding a treatment for a rare disease, a commitment to longitudinal care of patients allows one to establish the phenotype and natural history of the disease and the creation of a collaboration scientific team is critical. The ability to conduct clinical research for rare diseases has changed dramatically in the past two decades resulting in increased understanding of the basis of these disorders leading to direct benefit to patients.
Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K, Merkel PA, Rare Diseases Clinical Research Network Molecular Genetics and Metabolism2009
Bile acids work as natural detergents to help the body break down and use the fats and vitamins taken in as food. They are chemicals made by the liver that start as cholesterol and are converted to their final form through a progressive series of steps. Each step in this path requires a special protein, or enzyme, to occur correctly. An inborn error of bile acid synthesis, an inherited condition, occurs if one of these enzymes is defective. There are 9 known errors of bile acid synthesis, which can cause abnormal liver tests, jaundice, neurologic problems, and severe vitamin deficiencies. If diagnosed early, patients may respond well to medical therapy. This paper carefully reviews the chemical pathway of bile acid synthesis, along with the clinical presentation, diagnosis and treatment of each known error of bile acid synthesis.
Sundaram SS, Bove KE, Lovell MA, Sokol RJNature Clinical Practice: Gastroenterology & Hepatology2008
Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families
Strautnieks SS, Bryne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozcay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Nemeth A, Kotalova R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jamkowska I, Pawlowska J, Mieli-Vergani G, Knisely AS, Bull LN, Thompson RJGastroenterology2008
Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early need for transplantation or death in children with biliary atresia was determined. Growth velocity was significantly slower in infants with poor bile flow compared to those with good bile flow after the Kasai procedure.
DeRusso PA, Ye W, Shepherd R, Haber B, Sheider BL, Whitington PF, Schwarz KB, Bezerra JA, Rosenthal P, Karpen SJ, Squires RH, Magee JC, Robuck P, Sokol RJ, Biliary Atresia Research Consortium Hepatology2007
Nine recognized inborn errors of bile acid metabolism have been identified which lead to enzyme deficiencies and impaired bile acid synthesis in infants, children and adults. Patients may present with neonatal jaundice due to liver disease, neurologic disease, or fat and fat soluble vitamin malabsorption. This review focuses on a description of the disorders of bile acid synthesis that are directly related to single defects in the metabolic pathway and summarizes the clinical, biochemical, liver biopsy findings, clinical course and response to oral bile acid with either cholic acid or glycocholic acid.
Heubi J, Setchell KD, Bove KESeminars in Liver Disease2007
Liver involvement is a common feature in childhood mitochondrial disorders, particularly those that present in the newborn period and in infants. Nervous system, muscle and heart involvement are common and a key finding is the presence of elevated blood lactate levels.. The liver disease usually progresses and is not infrequently fatal. Current medical therapy of mitochondrial liver disorders is largely ineffective. The role of liver transplantation in patients with mitochondrial diseases is not clear because features outside of the liver do not respond to transplantation. Recent advances have led to discovery of new genetic causes of these diseases, including the following genes: SCO1, BCS1L, POLG, DGUOK, and MPV17 and deletion or rearrangement of mitochondrial DNA. Large multicenter studies will be needed to address the gaps in our knowledge in these rare liver diseases.
Lee WS, Sokol RJSeminars in Liver Disease2007
This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006 in Bethesda, MD, that addressed the issues of outcomes, screening and pathogenesis of biliary atresia.
Sokol RJ, Shepherd R, Superina R, Bezerra JA, Hoofnagle JHJournal of Hepatology2007
The acyl-CoA dehydrogenases are a family of multimeric flavoenzymes that catalyze the alpha,beta -dehydrogenation of acyl-CoA esters in fatty acid beta -oxidation and amino acid catabolism. Genetic defects have been identified in most of the acyl-CoA dehydrogenases in humans. Acyl-CoA dehydrogenase 9 (ACAD9) is a recently identified acyl-CoA dehydrogenase that demonstrates maximum activity with unsaturated long-chain acyl-CoAs. We now report the first three cases of ACAD9 deficiency.
He M, Rutledge SL, Kelly DR, Palmer CA, Murdoch G, Majumder N, Nicholls RD, Pei Z, Watkins PA, Vockley JAmerican Journal of Human Genetics2007
Biliary atresia is associated with oligoclonal expansions of CD4+ and CD8+ T cells within liver and extrahepatic bile duct remnant tissues, indicating the presence of activated T cells reacting to specific antigenic stimulation. Future studies entail identifying the specific antigen(s) responsible for T-cell activation and bile duct injury.
Mack CL, Falta MT, Sullivan AK, Karrer F, Sokol RJ, Fontenot APGastroenterology2007
Shneider BL, Bezerra JA, Sokol RJ, Whitington PFJournal of Pediatrics2007
Defects in bile acid biosynthesis--diagnosis and treatment.
Setchell KD, Heubi JJournal of Pediatric Gastroenterology and Nutrition2006
The objective of the study is to determine the prognostic factors and optimal approaches to the diagnosis and management of biliary atresia, the leading indication for liver transplantation in children. The outcome in the study centers was equivalent to that reported in other countries. Total bilirubin in early follow-up (3 months) after hepatoportoenterostomy was highly predictive of outcome. Efforts to improve bile flow after hepatoportoenterostomy may lead to improved outcome in children with biliary atresia.
Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires RH, Bezerra JA, Shepherd R, Rosenthal P, Hoofnagle JH, Sokol RJ, Biliary Atresia Research Consortium Journal of Pediatrics2006
The authors report the development of a high-throughput re-sequencing chip that efficiently reads SERPINA1, JAG1, ATP8B1, ABCB11 and ABCB4, with a high call rate and accuracy. Bench-testing of the chip in normal and diseased subjects identified disease-causing mutations.
Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R, Bezerra JAGastroenterology2006
Biliary Atresia Research Consortium (BARC).
Hoofnagle JHJournal of Hepatology2004
The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health of the United States (NIDDK) has initiated funding of a 5-year, multicenter study of biliary atresia, neonatal hepatitis, and related neonatal liver diseases. The overall goal of this consortium is to gather clinical and biochemical data and adequate numbers of serum, tissue and DNA samples in a prospective manner to facilitate research and generate new hypotheses and test existing hypotheses on the pathogenesis and optimal diagnostic and treatment modalities of these disorders.
Sokol RJJournal of Pediatric Gastroenterology and Nutrition2003