Browsing by Author "Karpen, Saul J."

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    Extrahepatic anomalies in infants with biliary atresia: results of a large prospective North American multicenter study
    (Wiley, 2013-11) Schwarz, Kathleen B.; Haber, Barbara H.; Rosenthal, Philip; Mack, Cara L; Moore, Jeffrey; Bove, Kevin E.; Bezerra, Jorge A.; Karpen, Saul J.; Kerkar, Nanda; Shneider, Benjamin L.; Turmelle, Yumirle P.; Whitington, Peter F.; Molleston, Jean P.; Murray, Karen F.; Ng, Vicky L.; Romero, René; Wang, Kasper S.; Sokol, Ronald J.; Magee, John C.; Pediatrics, School of Medicine
    Background and aims The etiology of biliary atresia (BA) is unknown. Given that patterns of anomalies might provide etiopathogenetic clues, we utilized data from the North American Childhood Liver Disease Research and Education Network to analyze patterns of anomalies in infants with BA. Methods Two hundred eighty-nine infants who were enrolled into the prospective database prior to surgery at any of 15 centers participating were evaluated. Results Group 1 was non-syndromic, isolated BA (without major malformations) (n = 242, 84 %), Group 2 was BA and at least one malformation considered major as defined by the National Birth Defects Prevention Study but without laterality defects (n = 17, 6%). Group 3 was syndromic, with laterality defects (n = 30, 10%). In the population as a whole, anomalies (either major or minor) were most prevalent in the cardiovascular (16%) and gastrointestinal (14%) systems. Group 3 patients accounted for the majority of subjects with cardiac, gastrointestinal and splenic anomalies. Group 2 subjects also frequently displayed cardiovascular (71%) and gastrointestinal (24 %) anomalies; interestingly this group had genitourinary anomalies more frequently (47%) compared to Group 3 subjects (10%). Conclusions This study identified a group of BA (Group 2) that differed from the classical syndromic and non-syndromic groups and that was defined by multiple malformations without laterality defects. Careful phenotyping of the patterns of anomalies may be critical to the interpretation of both genetic and environmental risk factors associated with BA, allowing new insight into pathogenesis and/or outcome.
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    Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome
    (Wiley, 2019) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of Medicine
    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 — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome.
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    Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome
    (Wiley, 2019-01-21) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of Medicine
    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 — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the NIDDK-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre-specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi-allelic variants in polycystin 1-like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non-cholestatic diseases. Conclusion: WES identified bi-allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.
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    Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial
    (Elsevier, 2018-11) Alonso, Estella M.; Ye, Wen; Hawthorne, Kieran; Venkat, Veena; Loomes, Kathleen M.; Mack, Cara L.; Hertel, Paula M.; Karpen, Saul J.; Kerkar, Nanda; Molleston, Jean P.; Murray, Karen F.; Romero, Rene; Rosenthal, Philip; Schwarz, Kathleen B.; Shneider, Benjamin L.; Suchy, Frederick J.; Turmelle, Yumirle P.; Wang, Kasper S.; Sherker, Averell H.; Sokol, Ronald J.; Bezerra, Jorge A.; Magee, John C.; Pediatrics, School of Medicine
    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 biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants. STUDY DESIGN: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age. RESULTS: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life. CONCLUSIONS: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage.
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    Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study
    (Elsevier, 2018-05) Ng, Vicky L.; Sorensen, Lisa G.; Alonso, Estella M.; Fredericks, Emily M.; Ye, Wen; Moore, Jeff; Karpen, Saul J.; Shneider, Benjamin L.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Loomes, Kathleen M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper; Arnon, Ronen; Schwarz, Kathleen B.; Turmelle, Yumirle P.; Haber, Barbara H.; Sherker, Averell H.; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of Medicine
    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 neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and <85 for χ2 analysis. Risk for neurodevelopmental impairment (defined as ≥1 score of <85 on the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition, scales) was analyzed using logistic regression. RESULTS: There were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P < .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P < .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age. CONCLUSION: Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are >4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions.
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    Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study
    (Wiley, 2020-03) Kamath, Binita M.; Ye, Wen; Goodrich, Nathan P.; Loomes, Kathleen M.; Romero, Rene; Heubi, James E.; Leung, Daniel H.; Spinner, Nancy B.; Piccoli, David A.; Alonso, Estella M.; Guthery, Stephen L.; Karpen, Saul J.; Mack, Cara L.; Molleston, Jean P.; Murray, Karen F.; Rosenthal, Philip; Squires, James E.; Teckman, Jeffrey; Wang, Kasper S.; Thompson, Richard; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of Medicine
    Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of <−1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height z‐score by 0.10 (P = 0.03) and weight z‐score by 0.15 (P = 0.007). Total bilirubin was higher for younger participants (P = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within‐individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant–free survival at the age of 18.5 years was 24%. Conclusions: This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.
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    Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia
    (Elsevier, 2016-03) Shneider, Benjamin L.; Magee, John C.; Karpen, Saul J.; Rand, Elizabeth B.; Narkewicz, Michael R.; Bass, Lee M.; Schwarz, Kathleen; Whitington, Peter F.; Bezerra, Jorge A.; Kerkar, Nanda; Haber, Barbara; Rosenthal, Philip; Turmelle, Yumirle P.; Molleston, Jean P.; Murray, Karen F.; Nguyen, Vicky L.; Wang, Kasper S.; Romero, Rene; Squires, Robert H.; Arnon, Ronen; Sherker, Averell H.; Moore, Jeffrey; Ye, Wen; Sokol, Ronald J.; Department of Pediatrics, IU School of Medicine
    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 enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB <2.0, all others TB ≥ 2) after HPE was examined as a biomarker, using Kaplan-Meier survival and logistic regression. RESULTS: Fifty percent (68/137) of infants had TB < 2.0 in the first 3 months after HPE. Transplant-free survival at 2 years was significantly higher in the TB < 2.0 group vs TB ≥ 2 (86% vs 20%, P < .0001). Infants with TB ≥ 2 had diminished weight gain (P < .0001), greater probability of developing ascites (OR 6.4, 95% CI 2.9-14.1, P < .0001), hypoalbuminemia (OR 7.6, 95% CI 3.2-17.7, P < .0001), coagulopathy (OR 10.8, 95% CI 3.1-38.2, P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P < .0001), or LT or death (OR 16.8, 95% CI 7.2-39.2, P < .0001). CONCLUSIONS: Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB <2.0 mg/dL within 3 months of HPE may enhance early outcomes.