IU Indianapolis ScholarWorks :: Browsing by Author "Alonso, Estella M."

Browsing by Author "Alonso, Estella M."

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Baseline ultrasound and clinical correlates in children with cystic fibrosis.
(Elsevier, 2015-10) Leung, Daniel H.; Ye, Wen; Molleston, Jean P.; Weymann, Alexander; Ling, Simon; Paranjape, Shruti M.; Romero, Rene; Schwarzenberg, Sara Jane; Palermo, Joseph; Alonso, Estella M.; Murray, Karen F.; Marshall, Bruce C.; Sherker, Averell H.; Siegel, Marilyn J.; Krishnamurthy, Rajesh; Harned, Roger; Karmazyn, Boaz; Magee, John C.; Narkewicz, Michael R.; Department of Pediatrics, IU School of Medicine
Objective: To investigate the relationship between abdominal ultrasound (US) findings and demographic, historical and clinical features in children with CF. Study design: Children age 3-12 years with CF without known cirrhosis, were enrolled in a prospective, multi-center study of US to predict hepatic fibrosis. Consensus US patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and U.S. or Toronto CF registries. Chi-square or ANOVA were used to compare variables among US groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal US. Results: Findings in 719 subjects were normal (n=590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis (p=0.0004), homogeneous (p<0.0001) and heterogeneous (p=0.03) were older than normal. More males were heterogeneous (p=0.001). More heterogeneous (15.0%, p=0.009) and cirrhosis (25.0%, p=0.005) had
Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study
(Elsevier, 2020-04) Siegel, Marilyn J.; Freeman, A. Jay; Ye, Wen; Palermo, Joseph J.; Molleston, Jean P.; Paranjape, Shruti M.; Stoll, Janis; Leung, Daniel; Masand, Prakash; Karmazyn, Boaz; Harned, Roger; Ling, Simon C.; Navarro, Oscar M.; Karnsakul, Wikrom; Alazraki, Adina; Schwarzenberg, Sarah Jane; Seidel, F. Glen; Towbin, Alex; Alonso, Estella M.; Nicholas, Jennifer L.; Murray, Karen F.; Otto, Randolph K.; Sherker, Averell H.; Magee, John C.; Narkewicz, Michael R.; Pediatrics, School of Medicine
Objective: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease. Study design: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease. Results: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern). Conclusions: Research liver ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.
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.
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.
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.
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.
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.
Variceal Hemorrhage and Adverse Liver Outcomes in Patients With Cystic Fibrosis Cirrhosis
(Wolters Kluwer, 2018-01) Ye, Wen; Leung, Daniel H.; Karnsakul, Wikrom; Murray, Karen F.; Alonso, Estella M.; Magee, John C.; Schwarzenberg, Sarah Jane; Weymann, Alexander; Molleston, Jean P.; Narkewicz, Mark R.; Pediatrics, School of Medicine
OBJECTIVES: Cirrhosis occurs in 5% to 10% of cystic fibrosis (CF) patients, often accompanied by portal hypertension. We analyzed 3 adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver-related death (LD), and risk factors for these in CF Foundation Patient Registry subjects with reported cirrhosis. METHODS: We determined 10-year incidence rates for VB, LT, LD, and all-cause mortality (ACM), and examined risk factors using competing risk models and Cox-proportional hazard regression. RESULTS: From 2003 to 2012, 943 participants (41% females, mean age 18.1 years) had newly reported cirrhosis; 24.7% required insulin, 85% had previous pseudomonas. Seventy-three subjects had reported VB: 38 with first VB and new cirrhosis reported simultaneously and 35 with VB after cirrhosis report. Ten-year cumulative VB, LT, and LD rates were 6.6% (95% confidence interval [CI]: 4.0, 9.1%), 9.9% (95% CI: 6.6%, 13.2%), and 6.9% (95% CI: 4.0%, 9.8%), respectively, with an ACM of 39.2% (95% CI: 30.8, 36.6%). ACM was not increased in subjects with VB compared to those without (hazard ratio [HR] 1.10, 95% CI: 0.59, 2.08). CF-related diabetes (HR: 3.141, 95% CI:1.56, 6.34) and VB (HR: 4.837, 95% CI: 2.33, 10.0) were associated with higher LT risk, whereas only worse lung function was associated with increased LD in multivariate analysis. Death rate among subjects with VB was 24% with LT and 20.4% with native liver. CONCLUSIONS: VB is an uncommon complication of CF cirrhosis and can herald the diagnosis, but does not affect ACM. Adverse liver outcomes and ACM are frequent by 10 years after cirrhosis report.

Browsing by Author "Alonso, Estella M."

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