Published Research

Total Records: 99; Page 1 of 5
TitleMediaAuthorsPublicationPublication Year Descending order
Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease
Leung DH, Devaraj S, Goodrich NP, Chen X, Rajapakshe D, Ye W, Andreev VP, Minard CG, Guffey D, Molleston JP, Bass LM, Karpen SJ, Kamath BM, Wang KS, Sundaram SS, Rosenthal P, McKiernan P, Loomes KM, Jensen MK, Horslen SP, Bezerra JA, Magee JC, Merion RM, Sokol RJ, Shneider BL, Childhood Liver Disease Research and Education Net
Hepatology (2022)
Leung DH, Devaraj S, Goodrich NP, Chen X, Rajapakshe D, Ye W, Andreev VP, Minard CG, Guffey D, Molleston JP, Bass LM, Karpen SJ, Kamath BM, Wang KS, Sundaram SS, Rosenthal P, McKiernan P, Loomes KM, Jensen MK, Horslen SP, Bezerra JA, Magee JC, Merion RM, Sokol RJ, Shneider BL, Childhood Liver Disease Research and Education Net Hepatology2022
Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome
Shneider BL, Spino C, Kamath BM, Magee JC, Ignacio RV, Huang S, Horslen S, Molleston JP, Miethke A, Kohli R, Leung DH, Jensen MK, Loomes KM, Karpen SJ, Mack CL, Rosenthal P, Squires RH, Baker A, Rajwal S, Kelly D, Sokol RJ, Thompson RJ, ChiLDReN , UK IMAGO/IMAGINE Investigators
Hepatology Communications (2022)
Shneider BL, Spino C, Kamath BM, Magee JC, Ignacio RV, Huang S, Horslen S, Molleston JP, Miethke A, Kohli R, Leung DH, Jensen MK, Loomes KM, Karpen SJ, Mack CL, Rosenthal P, Squires RH, Baker A, Rajwal S, Kelly D, Sokol RJ, Thompson RJ, ChiLDReN , UK IMAGO/IMAGINE Investigators Hepatology Communications2022
Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome
Shneider BL, Kamath BM, Magee JC, Goodrich NP, Loomes KM, Ye W, Spino C, Alonso EM, Molleston JP, Bezerra JA, Wang KS, Karpen SJ, Horslen S, Guthery SL, Rosenthal P, Squires RH, Childhood Liver Disease Research and Education Net
Hepatology Communications (2022)
Shneider BL, Kamath BM, Magee JC, Goodrich NP, Loomes KM, Ye W, Spino C, Alonso EM, Molleston JP, Bezerra JA, Wang KS, Karpen SJ, Horslen S, Guthery SL, Rosenthal P, Squires RH, Childhood Liver Disease Research and Education Net Hepatology Communications2022
Risk of variceal hemorrhage and pretransplant mortality in children with biliary atresia
Bass LM, Ye W, Hawthorne K, Leung DH, Murray KF, Molleston JP, Romero R, Karpen SJ, Rosenthal P, Loomes KM, Wang KS, Squires RH, Miethke A, Ng VL, Horslen SP, Jensen MK, Sokol RJ, Magee JC, Shneider BL, Childhood Liver Disease Research and Education Net
Hepatology (2022)
Bass LM, Ye W, Hawthorne K, Leung DH, Murray KF, Molleston JP, Romero R, Karpen SJ, Rosenthal P, Loomes KM, Wang KS, Squires RH, Miethke A, Ng VL, Horslen SP, Jensen MK, Sokol RJ, Magee JC, Shneider BL, Childhood Liver Disease Research and Education Net Hepatology2022
To evaluate the neurodevelopmental status of children with inherited cholestatic liver diseases and features to predict impairment. Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85–99, 70–84, <70). Univariate linear regression was performed to study association between FSIQ and risk factors, stratified by disease. Two hundred and fifteen completed testing (ALGS n = 70, PFIC n = 43, A1AT n = 102); median age was 7.6 years (3.0–16.9). Mean FSIQ in ALGS was lower than A1AT (94 vs 101, P = 0.01). Frequency of FSIQ < 85 (>1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ. Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions.
Leung DH, Sorensen LG, Ye W, Hawthorne K, Ng VL, Loomes KM, Fredericks EM, Alonso EM, Heubi JE, Horslen SP, Karpen SJ, Molleston JP, Rosenthal P, Sokol RJ, Squires RH, Wang KS, Kamath BM, Magee JC
Journal of Pediatric Gastroenterology and Nutrition (2022)
Leung DH, Sorensen LG, Ye W, Hawthorne K, Ng VL, Loomes KM, Fredericks EM, Alonso EM, Heubi JE, Horslen SP, Karpen SJ, Molleston JP, Rosenthal P, Sokol RJ, Squires RH, Wang KS, Kamath BM, Magee JCJournal of Pediatric Gastroenterology and Nutrition2022
To determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multi-center cohort of infants. We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age. Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution, partial resolution, and exited healthy. Biochemical resolution occurred at median of 9 months of age. GGT was < 100 U/L at baseline in 34/83 participants (41%). Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely due to recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis. This warrants further study.
Hertel PM, Hawthorne K, Kim S, Finegold MJ, Shneider BL, Squires JE, Gupta NA, Bull LN, Murray KF, Kerkar N, Ng VL, Molleston JP, Bezerra JA, Loomes KM, Taylor SA, Schwarz KB, Turmelle YP, Rosenthal P, Magee JC, Sokol RJ, Childhood Liver Disease Research and Education Net
Journal of Pediatric Gastroenterology and Nutrition (2021)
Hertel PM, Hawthorne K, Kim S, Finegold MJ, Shneider BL, Squires JE, Gupta NA, Bull LN, Murray KF, Kerkar N, Ng VL, Molleston JP, Bezerra JA, Loomes KM, Taylor SA, Schwarz KB, Turmelle YP, Rosenthal P, Magee JC, Sokol RJ, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2021
Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. Ninety-eight participants with FIC1, BSEP, or MDR3 deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.
Hertel PM, Bull LN, Thompson RJ, Goodrich NP, Ye W, Magee JC, Squires RH, Bass LM, Heubi JE, Kim GE, Ranganathan S, Schwarz KB, Bozic MA, Horslen SP, Clifton MS, Turmelle YP, Suchy FJ, Superina RA, Wang KS, Loomes KM, Kamath BM, Sokol RJ, Shneider BL
Journal of Pediatric Gastroenterology and Nutrition (2021)
Hertel PM, Bull LN, Thompson RJ, Goodrich NP, Ye W, Magee JC, Squires RH, Bass LM, Heubi JE, Kim GE, Ranganathan S, Schwarz KB, Bozic MA, Horslen SP, Clifton MS, Turmelle YP, Suchy FJ, Superina RA, Wang KS, Loomes KM, Kamath BM, Sokol RJ, Shneider BLJournal of Pediatric Gastroenterology and Nutrition2021
Elastographic measurement of liver stiffness is of growing importance in the assessment of liver disease. Pediatric experiences with this technique are primarily single center and limited in scope. The Childhood Liver Disease Research Network provided a unique opportunity to assess elastography in a well-characterized multi-institutional cohort. Children with biliary atresia (BA), alpha-1 antitrypsin deficiency (A1ATD), or Alagille syndrome (ALGS) followed in a prospective longitudinal network study were eligible for enrollment in a prospective investigation of transient elastography (FibroScan). Studies were performed in participants who were nonfasted and nonsedated. Liver stiffness measurements (LSMs) were correlated with standard clinical and biochemical parameters of liver disease along with a research definition of clinically evident portal hypertension (CEPH) graded as absent, possible, or definite. Between November 2016 and August 2019, 550 participants with a mean age of 8.8 years were enrolled, 458 of whom had valid LSMs. Invalid scans were more common in participants <2 years old. There was a positive correlation between LSM and total bilirubin, international normalized ratio (INR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), GGT to platelet ratio (GPR), pediatric end-stage liver disease score, AST to platelet ratio index, and spleen size, and a negative correlation with albumin and platelet count in BA, with similar correlations for A1ATD (except AST, ALT, and albumin) and ALGS (except for INR, GGT, GPR, and ALT). Possible or definite CEPH was more common in BA compared to ALGS and A1ATD. LSM was greater in definite versus absent CEPH in all three diseases. Disease-specific clinical and biochemical characteristics of the different CEPH grades were observed. It is feasible to obtain LSMs in children, especially over the age of 2 years. LSM correlates with liver parameters and portal hypertension, although disease-specific patterns exist.
Shneider BL, Goodrich NP, Ye W, Sawyers C, Molleston JP, Merion RM, Leung DH, Karpen SJ, Kamath BM, Cavallo LA, Wang K, Teckman JH, Squires JE, Sundaram SS, Rosenthal P, Romero R, Murray KF, Loomes KM, Jensen MK, Bezerra JA, Bass LM, Sokol RJ, Magee JC
Hepatology Communications (2020)
Shneider BL, Goodrich NP, Ye W, Sawyers C, Molleston JP, Merion RM, Leung DH, Karpen SJ, Kamath BM, Cavallo LA, Wang K, Teckman JH, Squires JE, Sundaram SS, Rosenthal P, Romero R, Murray KF, Loomes KM, Jensen MK, Bezerra JA, Bass LM, Sokol RJ, Magee JCHepatology Communications2020
Approximately 50% of infants with biliary atresia (BA) undergoing Kasai portoenterostomy show survival with native liver (SNL) at age 2 years. Predictors of disease progression after age 2 years are unknown, despite estimates of 20%-30% undergoing liver transplant (LT) between age 2 and 18 years. We sought to address this knowledge gap by developing prognostic models in participants of the multicenter prospective National Institutes of Health-supported Childhood Liver Disease Research Network. We extracted 14 clinical and biochemical variables at age 2 years to develop two models for future outcomes: 1) LT or death (LTD) and 2) first sentinel event (SE), either new onset ascites, hepatopulmonary syndrome (HPS), or gastrointestinal (GI) bleed. A total of 240 participants, enrolled between 2004 and 2017, were followed until a median age of 5.1 years (range, 2.0-13.3 years). Of these participants, 38 underwent LT (n = 37) or death (n = 1); cumulative incidence, 23.7%. Twenty-seven experienced either new-onset ascites (n = 13), HPS (n = 1), or GI bleed (n = 14). One participant had ascites and GI bleed concurrently; cumulative incidence, 21.5% by age 10 years. The Cox proportional hazard model predicted risk of LTD, using total bilirubin, albumin, platelet count, and history of either ascites or cholangitis (BA LTD model), with a C-index of 0.88 (range, 0.86-0.89). A cause-specific hazard competing risk model predicted SE using platelet count and gamma glutamyltransferase levels (BA SE model) with a C-index of 0.81. Internal model validity was assessed using Harrell's C-index with cross-validation. Stratification using these models identified risk of poor outcomes in patients with BA SNL after age 2 years. The models may identify those who would benefit from enhanced clinical surveillance and prioritization in clinical trials.
Venkat VL, Ng VL, Magee JC, Ye W, Hawthorne K, Harpavat S, Molleston JP, Murray KF, Wang KS, Soufi N, Bass LM, Alonso EM, Bezerra JA, Jensen MK, Kamath BM, Loomes KM, Mack CL, Rosenthal P, Shneider BL, Squires RH, Sokol RJ, Karpen SJ
Hepatology Communications (2020)
Venkat VL, Ng VL, Magee JC, Ye W, Hawthorne K, Harpavat S, Molleston JP, Murray KF, Wang KS, Soufi N, Bass LM, Alonso EM, Bezerra JA, Jensen MK, Kamath BM, Loomes KM, Mack CL, Rosenthal P, Shneider BL, Squires RH, Sokol RJ, Karpen SJHepatology Communications2020
To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.
Teckman JH, Rosenthal P, Hawthorne K, Spino C, Bass LM, Murray KF, Kerkar N, Magee JC, Karpen SJ, Heubi JE, Molleston JP, Squires RH, Kamath BM, Guthery SL, Loomes KM, Sherker AH, Sokol RJ
Journal of Pediatrics (2020)
Teckman JH, Rosenthal P, Hawthorne K, Spino C, Bass LM, Murray KF, Kerkar N, Magee JC, Karpen SJ, Heubi JE, Molleston JP, Squires RH, Kamath BM, Guthery SL, Loomes KM, Sherker AH, Sokol RJJournal of Pediatrics2020
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.
Kamath BM, Ye W, Goodrich NP, Loomes KM, Romero R, Heubi JE, Leung DH, Spinner NB, Piccoli DA, Alonso EM, Guthery SL, Karpen SJ, Mack CL, Molleston JP, Murray KF, Rosenthal P, Squires JE, Teckman JH, Wang KS, Thompson RJ, Magee JC, Sokol RJ, Childhood Liver Disease Research and Education Net
Hepatology Communications (2020)
Kamath BM, Ye W, Goodrich NP, Loomes KM, Romero R, Heubi JE, Leung DH, Spinner NB, Piccoli DA, Alonso EM, Guthery SL, Karpen SJ, Mack CL, Molleston JP, Murray KF, Rosenthal P, Squires JE, Teckman JH, Wang KS, Thompson RJ, Magee JC, Sokol RJ, Childhood Liver Disease Research and Education Net Hepatology Communications2020
Pruritus is a debilitating symptom for patients with Alagille syndrome (ALGS). In a previously reported trial of maralixibat, an investigational antipruritic agent, itching was assessed using a digital diary based on twice-daily caregiver observation of itching severity (Itch Reported Outcome, ItchRO). The goal of this study was to characterize pruritus in participants with ALGS at baseline in this trial, as assessed by the ItchRO instrument and the physician-observed clinician scratch scale (CSS), relative to biomarkers putatively associated with pruritus and health-related quality of life assessment. Thirty-seven participants with ALGS (median age of 6 years; range 1-17 years) were enrolled. No association was identified between CSS and ItchRO(Obs). Neither CSS nor ItchRO were associated with serum bile acids or autotaxin. There was no significant association between Pediatric Quality of Life Inventory total parent scores and CSS or ItchRO. There was a significant association between ItchRO and Multidimensional Fatigue Scale and Family Impact Module total scores. In exploratory analysis, selected questions relating to fatigue and sleep disturbance (n = 12) from Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale, and Family Impact Module were correlated with pruritus scores; positive associations were identified. Conclusion: Itching scores did not correlate with each other, nor with putative serum biomarkers of pruritus, and further, did not correlate with quality of life. Hypothesis-generating analyses implicate sleep disturbance and fatigue as key associations with caregiver observations of itching. This is highly relevant to the selection of surrogate endpoints for clinical trials of pruritus therapies.
Kamath BM, Spino C, McLain R, Magee JC, Fredericks EM, Setchell KD, Miethke A, Molleston JP, Mack CL, Squires RH, Alonso EM, Murray KF, Loomes KM, Jensen MK, Karpen SJ, Rosenthal P, Thomas DW, Sokol RJ, Shneider BL
Hepatology Communications (2020)
Kamath BM, Spino C, McLain R, Magee JC, Fredericks EM, Setchell KD, Miethke A, Molleston JP, Mack CL, Squires RH, Alonso EM, Murray KF, Loomes KM, Jensen MK, Karpen SJ, Rosenthal P, Thomas DW, Sokol RJ, Shneider BLHepatology Communications2020
The aim of the study was to assess neurodevelopmental outcomes among children with biliary atresia (BA) surviving with their native liver at ages 3 to 12 years and evaluate variables that associate with neurodevelopment. Participants (ages 3-12 years) in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with Weschler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III, ages 3-5 years) and Weschler Intelligence Scale for Children, 4th edition (WISC-IV, ages 6-12 years). Continuous scores were analyzed using Kolmogorov-Smironov tests compared with a normal distribution (mean = 100 ± 15). Effect of covariates on Full-Scale Intelligence Quotient (FSIQ) was analyzed using linear regression. Ninety-three participants completed 164 WPPSI-III (mean age 3.9) and 51 WISC-IV (mean age 6.9) tests. WPPSI-III FSIQ (104 ± 14, P < 0.02), Verbal IQ (106 ± 14, P < 0.001), and General Language Composite (107 ± 16, P < 0.001) distributions were shifted higher compared with test norms. WISC-IV FSIQ (105 ± 12, P < 0.01), Perceptual Reasoning Index (107 ± 12, P < 0.01), and Processing Speed Index (105 ± 10, P < 0.02) also shifted upwards. In univariate and multivariable analysis, parent education (P < 0.01) was a significant predictor of FSIQ on WPPSI-III and positively associated with WISC-IV FSIQ. Male sex and higher total bilirubin and gamma glutamyl transferase (GGT) predicted lower WPPSI-III FSIQ. Portal hypertension was predictive of lower WISC-IV FSIQ. This cohort of children with BA and native liver did not demonstrate higher prevalence of neurodevelopmental delays. Markers of advanced liver disease (higher total bilirubin and GGT for age ≤5 years; portal hypertension for age ≥6) correlate with lower FSIQ and may identify a vulnerable subset of patients who would benefit from intervention.
Squires JE, Ng VL, Hawthorne K, Henn LL, Sorensen LG, Fredericks EM, Alonso EM, Murray KF, Loomes KM, Karpen SJ, Cavallo LA, Molleston JP, Bezerra JA, Rosenthal P, Squires RH, Wang KS, Schwarz KB, Arnon R, Magee JC, Sokol RJ, Childhood Liver Disease Research and Education Net
Journal of Pediatric Gastroenterology and Nutrition (2020)
Squires JE, Ng VL, Hawthorne K, Henn LL, Sorensen LG, Fredericks EM, Alonso EM, Murray KF, Loomes KM, Karpen SJ, Cavallo LA, Molleston JP, Bezerra JA, Rosenthal P, Squires RH, Wang KS, Schwarz KB, Arnon R, Magee JC, Sokol RJ, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2020
Portal hypertension (PHT) is a major cause of morbidity and mortality in pediatric liver diseases. Thus, research into causes and disease modifiers in PHT in these conditions is vitally important. PHT is rarely directly or indirectly measured in the assessment of children with chronic liver disease. A straightforward, reproducible definition of PHT could be invaluable for consistently identifying patients with PHT and for grouping these patients according to their risk of complications from their disease. We propose the term Clinically Evident Portal Hypertension (CEPH) to denote clinical findings that demonstrate evidence of elevated portal pressure. When CEPH criteria are met, PHT is highly likely to be present, although it is likely that PHT exists for variable periods of time before meeting CEPH criteria. Use of this research definition of CEPH will allow for consistent identification of these patients by clinicians in nearly any clinical setting and serve as a clinical milepost that may dictate future prognosis in pediatric patients with cirrhosis.
Bass LM, Shneider BL, Henn LL, Goodrich NP, Magee JC, Childhood Liver Disease Research and Education Net
Journal of Pediatric Gastroenterology and Nutrition (2019)
Bass LM, Shneider BL, Henn LL, Goodrich NP, Magee JC, Childhood Liver Disease Research and Education Net Journal of Pediatric Gastroenterology and Nutrition2019
Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T- and B-cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen-DR isotype [HLA-DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA-DR+CD38+ NK cells and expression of NK cell activation markers CD69 and HLA-DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)-8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA-DR+CD38+ NK cells and plasma IL-8 levels was associated with an increased risk of transplant or death by day 360. Conclusion: Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL-8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.
Kim SJ, Moore J, Alonso EM, Bendarek J, Bezerra JA, Goodhue C, Karpen SJ, Loomes KM, Magee JC, Ng VL, Sherker AH, Smith C, Spino C, Venkat VL, Wang K, Sokol RJ, Mack CL, ChiLDReN
Hepatology Communications (2019)
Kim SJ, Moore J, Alonso EM, Bendarek J, Bezerra JA, Goodhue C, Karpen SJ, Loomes KM, Magee JC, Ng VL, Sherker AH, Smith C, Spino C, Venkat VL, Wang K, Sokol RJ, Mack CL, ChiLDReN Hepatology Communications2019
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 National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified 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 biallelic variants in polycystic kidney disease 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 noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM 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
Hepatology (2019)
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
Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. A multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3-5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study. Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of -11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P > 0.05). Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver.
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 Nutrition (2019)
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
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. 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. 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. 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.
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 JC
Journal of Pediatrics (2018)
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
Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
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 RJ
Hepatology (2018)
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
Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors have been proposed. We performed a genome-wide association study (GWAS) in a European-American cohort of 343 isolated BA patients and 1716 controls to identify genetic loci associated with BA. A second GWAS was performed in an independent European-American cohort of 156 patients with BA and other extrahepatic anomalies and 212 controls to confirm the identified candidate BA-associated SNPs. Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1 (rs10865291, rs6761893, and rs727878; P < 5 ×10-8), located within the fifth intron of the EFEMP1 gene, which encodes a secreted extracellular protein implicated in extracellular matrix remodeling, cell proliferation, and organogenesis. RNA expression analysis showed an increase in EFEMP1 transcripts from human liver specimens isolated from patients with either BA or other cholestatic diseases when compared to normal control liver samples. Immunohistochemistry demonstrated that EFEMP1 is expressed in cholangiocytes and vascular smooth muscle cells in liver specimens from patients with BA and other cholestatic diseases, but it is absent from cholangiocytes in normal control liver samples. Efemp1 transcripts had higher expression in cholangiocytes and portal fibroblasts as compared with other cell types in normal rat liver. The identification of a novel BA-associated locus, and implication of EFEMP1 as a new BA candidate susceptibility gene, could provide new insights to understanding the mechanisms underlying this severe pediatric disorder.
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 M
PLOS Genetics (2018)
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
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