67 results on '"Harpavat S"'
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2. SAT-052 - Transcatheter recanalization with angioplasty and/or stenting: a novel, minimally-invasive treatment option for children with chronic portal vein thrombosis with cavernous transformation
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Justino, H., Kukreja, K., Hernandez, J.A., Pham, Y., Harpavat, S., Karam, L., Hertel, P., Carter, B., Shneider, B., and Miloh, T.
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- 2018
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3. Adolescent Fast Food Choices in the Era of the Menu Boards with Nutritional Information: A Study to Maximize Effectiveness
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Conkin, C., primary, Merrill, A., additional, and Harpavat, S., additional
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- 2012
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4. Taeniasis in an Adolescent With Chronic Anemia
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Harpavat, S, primary, Hicks, MJ, additional, and Chumpitazi, BP, additional
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- 2010
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5. Postoperative pain and other sequelae of dental rehabilitations performed on children under general anesthesia.
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Needleman HL, Harpavat S, Wu S, Allred EN, and Berde C
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- 2008
6. Independent Risk Factors and Economic Burden Associated With Delayed Extubation Following Pediatric Liver Transplantation.
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Virk MK, Coss-Bu J, Mian MUM, Nguyen Galvan NT, Sabapathy D, Castro D, Fogarty T, Hosek K, Beel ER, Schackman J, Harpavat S, Goss J, and Desai MS
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- Humans, Female, Male, Retrospective Studies, Child, Preschool, Risk Factors, Infant, Child, Follow-Up Studies, Prognosis, Length of Stay economics, Hospital Costs statistics & numerical data, Adolescent, Liver Transplantation economics, Liver Transplantation adverse effects, Airway Extubation economics, Airway Extubation adverse effects, Postoperative Complications economics
- Abstract
Background: Successful early extubation (EE) after liver transplant (LT) has been shown to reduce intensive care unit (ICU) and hospital length of stay and infectious, vascular, and sedation-related complications in adults. EE may not always be feasible in children, and many may require prolonged mechanical ventilation. Limited data exists regarding the candidacy of EE, risk factors, consequences, and hospital costs of delayed extubation (DE) in pediatric LT., Methods: We conducted a retrospective review to investigate predictive factors and associated costs of EE and DE in infants and children after orthotopic LT at our institution between 2011 and 2021., Results: Of 338 LT (median age 39 months, 54% females), 246 (73%) had EE (within 24 h of LT), while 27% had DE. Age < 1 year (p = 0.0019), diagnosis of biliary atresia (0.02), abnormal pre-LT echocardiogram (0.02), and patients with ongoing hospital admission before LT (0.0001) were independently associated with DE. Hospital costs were significantly (∼3-fold) higher (p < 0.0001) in the DE group. In addition, factors associated with increased total hospital costs were age < 1 year and hospitalization before LT., Conclusion: EE post-LT is feasible and merits a trial. The prevalence of DE though modest is associated with increased resource utilization and hospital costs. Children who can be extubated early and those at risk for DE can be identified pre-operatively for optimal planning and allocation of resources., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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7. Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort.
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Pandurangi S, Mourya R, Nalluri S, Fei L, Dong S, Harpavat S, Guthery SL, Molleston JP, Rosenthal P, Sokol RJ, Wang KS, Ng V, Alonso EM, Hsu EK, Karpen SJ, Loomes KM, Magee JC, Shneider BL, Horslen SP, Teckman JH, and Bezerra JA
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- Humans, Infant, Female, Male, Infant, Newborn, Cohort Studies, Cholestasis diagnosis, Cholestasis blood, Prospective Studies, Matrix Metalloproteinase 7 blood, Biliary Atresia diagnosis, Biliary Atresia blood, Biomarkers blood
- Abstract
Background and Aims: High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated the accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort., Approach and Results: MMP-7 was measured in serum samples of 399 infants with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays. The discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an AUROC of 0.90 (CI: 0.87-0.94). At cutoff 52.8 ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77-0.86), stool color = 0.68 (CI: 0.63-0.73), and pathology = 0.84 (CI: 0.76-0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+gamma-glutamyl transferase AUROC to 0.91 (CI: 0.88-0.95). Serum concentrations produced by time resolved fluorescence energy transfer differed from single-plex, with an optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs., Conclusions: Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in the evaluation of infants with cholestasis may simplify diagnostic algorithms and shorten the time to hepatoportoenterostomy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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8. Effectiveness of Cord blood as a Strategy to rule out Conjugated Hyperbilirubinemia.
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Kurtca M, Harpavat S, and Devaraj S
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Early detection of biliary atresia is crucial for timely intervention and improved outcomes in infants with elevated conjugated bilirubin levels. This study aims to investigate the viability of cord blood gas analysis as a novel method for assessing conjugated bilirubin levels. Infants with high heel stick levels also showed elevated cord blood bilirubin levels, indicating that cord blood testing could replace the need for repeat heel stick tests, especially benefiting low birth weight infants. Ongoing research, including larger cohorts and alternative bilirubin measurement methods, will further validate this innovative screening approach. Infants with biliary atresia have high conjugated bilirubin levels at birth. As a result, infants can be screened with newborn conjugated bilirubin measurements, to allow for early detection, timely treatment, and the best chances of delaying or even avoiding the need for a liver transplant [1]. An important limitation of screening, however, is that infants must undergo a separate blood test. To overcome this limitation, we investigated whether conjugated bilirubin measurements from cord blood could be useful., (Copyright © 2024 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved.)
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- 2024
9. Herbal and dietary supplement induced liver injury leading to hepatitis-associated severe aplastic anemia: A case report.
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Mercedes R, Harpavat S, Hertel PM, Sasa G, Kirk S, Patel K, and Mysore KR
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Herbal and dietary supplements (HDS) are a common etiology of drug induced liver injury and, specifically, Herbalife® supplements have been implicated. Hepatitis associated aplastic anemia (HAAA) is a rare and potentially fatal complication after acute hepatitis characterized by pancytopenia. While there have been rare cases of HDS leading to HAAA, no cases of Herbalife® induced liver injury leading to HAAA have been reported from this specific HDS. We report a unique case of severe aplastic anemia developing after sub-fulminant liver failure associated with chronic HDS use. This case illustrates the importance of warning the public about HDS as their use continues to increase. It is not only important to recognize HDS as etiology, but also for healthcare providers to carefully monitor these patients after resolution of liver injury for the development of HAAA., Competing Interests: Dr. Sanjiv Harpavat serves on a Data Safety Monitoring Board for a biliary atresia therapeutic trial, sponsored by Syneos Health. Dr. Rebecca Mercedes receives funding from the NIH T32 training grant number T32DK007664. All other authors declare no conflicts of interest relevant to this article to disclose., (© 2024 The Authors. JPGN Reports published by Wiley Periodicals LLC on behalf of The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
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- 2024
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10. Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.
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Mian MUM, Kennedy CE, Coss-Bu JA, Javaid R, Naeem B, Lam FW, Fogarty T 3rd, Arikan AA, Nguyen TC, Bashir D, Virk M, Harpavat S, Galvan NTN, Rana AA, Goss JA, Leung DH, and Desai MS
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- Infant, Humans, Child, Retrospective Studies, Risk Factors, Liver Cirrhosis etiology, Respiration, Artificial, Liver Transplantation adverse effects
- Abstract
Background: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT)., Methods: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort)., Results: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91)., Conclusion: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources., (© 2023 Wiley Periodicals LLC.)
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- 2024
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11. The DILI's in the Details: A 13-Year-Old With Abdominal Pain and Jaundice.
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Wong MSc CK, MacMath D, Mercedes R, Beer SS, Cerminara DN, and Harpavat S
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- Humans, Adolescent, Abdominal Pain etiology, Jaundice etiology
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- 2023
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12. Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.
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Sok P, Sabo A, Almli LM, Jenkins MM, Nembhard WN, Agopian AJ, Bamshad MJ, Blue EE, Brody LC, Brown AL, Browne ML, Canfield MA, Carmichael SL, Chong JX, Dugan-Perez S, Feldkamp ML, Finnell RH, Gibbs RA, Kay DM, Lei Y, Meng Q, Moore CA, Mullikin JC, Muzny D, Olshan AF, Pangilinan F, Reefhuis J, Romitti PA, Schraw JM, Shaw GM, Werler MM, Harpavat S, and Lupo PJ
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- Humans, Exome genetics, Homozygote, Parents, Case-Control Studies, Membrane Proteins genetics, Biliary Atresia epidemiology, Biliary Atresia genetics, Biliary Atresia diagnosis
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The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex., (© 2023 Wiley Periodicals LLC.)
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- 2023
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13. Biliary Atresia Remnants Revisited: Myogenesis, Hepatic Duct-Like Structures, and Fate of Peribiliary Glands.
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Bove KE, Finegold MJ, and Harpavat S
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- Infant, Humans, Child, Adolescent, Young Adult, Adult, Middle Aged, Aged, Hepatic Duct, Common pathology, Inflammation, Epithelium pathology, Epithelial Cells pathology, Biliary Atresia pathology
- Abstract
Purpose and Context: Proximal levels of excised remnants from youngest infants may reveal early features of biliary atresia (BA)., Method: A targeted IHC survey was applied to 34 most proximal 2 levels in 17 BA remnants excised at age 10-74 days including 7 = <30 days old and 6 control hepatic ducts (HD)., Key Results: Severity of inflammation and extent of active fibroplasia do not distinguish proximal remnants in younger (n = 7) and older (n = 10) infants. In 27/34 levels of 14/17 remnants, reactive stroma is focally SM-MHC-2 (+), marking smooth muscle myosin, termed reactive myogenesis (RM), that is absent in controls. RM facilitates identification of 3 novel hepatic duct remnants (HDR): an HD-like collagen collar lined by degenerating cholangiocytes (n = 5); erosion defects in loose reactive stroma (n = 14); solitary foci of hyperplastic squamoid epithelium (n = 4). Peribiliary glands are either hyperplastic or atretic and typically lack RM., Conclusion: Minimally inflammed end-stage lesions in BA remnants occur at youngest ages favoring prenatal onset. Three novel HDR are defined. RM, a useful surrogate for HDR, is a prevalent inappropriate stromal reaction in proximal remnants of uncertain biological significance. RM is the source of mature smooth muscle in BA remnants.
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- 2023
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14. Elevated bile acids are associated with left ventricular structural changes in biliary atresia.
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Virk MK, Mian MUM, Bashir DA, Wilkes JK, Schlingman T, Flores S, Kennedy C, Lam F, Arikan AA, Nguyen T, Mysore K, Galvan NTN, Coss-Bu J, Karpen SJ, Harpavat S, and Desai MS
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- Child, Humans, Female, Male, Liver Cirrhosis complications, Bile Acids and Salts, GTP-Binding Proteins, Biliary Atresia, Cardiomyopathies complications
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Background: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood., Methods: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5., Results: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry., Conclusion: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
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- 2023
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15. Characteristics of infections and their risk factors in children with biliary atresia.
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Shiau H, Schraw JM, Mysore K, Cavallo L, Harpavat S, Lupo PJ, Munoz FM, and Shneider BL
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- Humans, Child, Infant, Prognosis, Liver, Risk Factors, Retrospective Studies, Treatment Outcome, Biliary Atresia complications, Biliary Atresia surgery, Cholangitis complications
- Abstract
Background: Children with biliary atresia (BA) may experience various infections (e.g., cholangitis, bacteremia, and viral respiratory infections (VRI)) throughout their disease course. This study aimed to identify and describe these infections and their risk factors for development in children with BA., Methods: This retrospective observational study identified infections in children with BA using predefined criteria, including VRI, bacteremia with and without central line (CL), bacterial peritonitis, positive stool pathogens, urinary tract infections, and cholangitis. Infections were identified until liver transplant, death or last follow-up with native liver. Infection-free survival was estimated by Kaplan-Meier analysis. Logistic regression was used to estimate odds of infection per clinical characteristics. Cluster analysis was performed to identify patterns of infection development., Results: 48 of 65 (73.8%) children had ≥1 infection during their disease course (mean length of follow up: 40.2 months). Cholangitis (n = 30) and VRI (n = 21) were most common. Nearly half (45%) of all infections developed within 3-months of Kasai hepatoportoenterostomy. Kasai performed ≥45 days of life was associated with 3.5-fold increased risk of any infection (95% CI 1.2-11.4). Risk of VRI was inversely related to platelet count at 1-month post-Kasai (OR 0.5, 0.19-0.99). Cluster analysis of infectious patterns identified three unique cohorts of patients based on their infection history: no/few infections (n = 18), mostly cholangitis (n = 20) or mixed infections (n = 27)., Conclusion: Variability of infection risk exists amongst children with BA. Age at Kasai and platelet count are risk factors for future infections, suggesting that patients with more severe disease are at greater risk. Cirrhosis associated immune deficiency may exist in chronic pediatric liver disease and should be the subject of future investigations in order to optimize outcomes., Competing Interests: Declaration of Competing Interest No other disclosures or conflicts of interest were reported., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2023
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16. Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy.
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Harpavat S, Hawthorne K, Setchell KDR, Rivas MN, Henn L, Beil CA, Karpen SJ, Ng VL, Alonso EM, Bezerra JA, Guthery SL, Horslen S, Loomes KM, McKiernan P, Magee JC, Merion RM, Molleston JP, Rosenthal P, Thompson RJ, Wang KS, Sokol RJ, and Shneider BL
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- Infant, Humans, Child, Portoenterostomy, Hepatic, Prognosis, Bilirubin, Bile Acids and Salts, Biomarkers, Treatment Outcome, Retrospective Studies, Biliary Atresia surgery
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Background and Aims: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group., Approach and Results: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 μmol/L ( n = 43) or >40 μmol/L ( n = 94) groups. At 2 years of age, the ≤40 μmol/L compared with >40 μmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 μmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 μmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 μmol/L group ( p = 0.001)., Conclusions: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases.)
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- 2023
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17. Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease.
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Leung DH, Devaraj S, Goodrich NP, Chen X, Rajapakshe D, Ye W, Andreev V, 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, Alonso E, Bass L, Kelly S, Riordan M, Melin-Aldana H, Bezerra J, Bove K, Heubi J, Miethke A, Tiao G, Denlinger J, Chapman E, Sokol R, Feldman A, Mack C, Narkewicz M, Suchy F, Sundaram SS, Van Hove J, Garcia B, Kauma M, Kocher K, Steinbeiss M, Lovell M, Loomes KM, Piccoli D, Rand E, Russo P, Spinner N, Erlichman J, Stalford S, Pakstis D, King S, Squires R, Sindhi R, Venkat V, Bukauskas K, McKiernan P, Haberstroh L, Squires J, Rosenthal P, Bull L, Curry J, Langlois C, Kim G, Teckman J, Kociela V, Nagy R, Patel S, Cerkoski J, Molleston JP, Bozic M, Subbarao G, Klipsch A, Sawyers C, Cummings O, Horslen SP, Murray K, Hsu E, Cooper K, Young M, Finn L, Kamath BM, Ng V, Quammie C, Putra J, Sharma D, Parmar A, Guthery S, Jensen K, Rutherford A, Lowichik A, Book L, Meyers R, Hall T, Wang KS, Michail S, Thomas D, Goodhue C, Kohli R, Wang L, Soufi N, Thomas D, Karpen S, Gupta N, Romero R, Vos MB, Tory R, Berauer JP, Abramowsky C, McFall J, Shneider BL, Harpavat S, Hertel P, Leung D, Tessier M, Schady D, Cavallo L, Olvera D, Banks C, Tsai C, Thompson R, Doo E, Hoofnagle J, Sherker A, Torrance R, Hall S, Magee J, Merion R, Spino C, and Ye W
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- Humans, Child, Liver pathology, Matrix Metalloproteinase 7, Endoglin, Interleukin-8, Liver Cirrhosis diagnosis, Liver Cirrhosis pathology, Biomarkers, Cholestasis pathology, Liver Diseases pathology, Alagille Syndrome pathology, Elasticity Imaging Techniques
- Abstract
Background and Aims: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis., Approach and Results: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS., Conclusions: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important., (Copyright © 2023 American Association for the Study of Liver Diseases.)
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- 2023
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18. Acute liver failure and unique challenges of pediatric liver transplantation amidst a worldwide cluster of adenovirus-associated hepatitis.
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Banc-Husu AM, Moulton EA, Shiau H, Gutierrez Sanchez LH, Desai MS, Cerminara D, Munoz FM, Buffaloe LM, Valencia-Deray KG, Galvan NTN, Bhatnagar J, Estetter L, Rassaei N, Reagan-Steiner S, Wicker J, Dunn JJ, Allen CE, Patel KR, Harpavat S, Goss JA, and Leung DH
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- Child, Humans, Adenoviridae, Liver Transplantation adverse effects, Adenovirus Infections, Human, Gastroenteritis, Liver Failure, Acute etiology, Liver Failure, Acute surgery
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Investigation into a recent cluster of acute hepatitis in children from the southeastern United States identified human adenovirus (HAdV) DNAemia in all 9 cases. Molecular genotyping in 5 of 9 (56%) children identified HAdV type 41 in all cases (100%). Importantly, 2 children from this cluster progressed rapidly to pediatric acute liver failure (PALF) and required liver transplantation. HAdV type 41, a known cause of self-limited gastroenteritis, has not previously been associated with severe cholestatic hepatitis and liver failure in healthy children. Adenovirus polymerase chain reaction assay and sequencing of amplicons performed on DNA extracted from formalin-fixed, paraffin-embedded liver tissue also identified adenovirus species F (HAdV type 40 or 41) in these 2 children with PALF. Transplant considerations and successful liver transplantation in such situations remain scarce. In this report, we describe the clinical course, laboratory results, liver pathology, and treatment of 2 children with PALF associated with HAdV type 41, one of whom developed secondary hemophagocytic lymphohistiocytosis. Their successful posttransplant outcomes demonstrate the importance of early multidisciplinary medical management and the feasibility of liver transplantation in some children with PALF and HAdV DNAemia., (Copyright © 2022. Published by Elsevier Inc.)
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- 2023
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19. The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease.
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Shearn CT, Anderson AL, Devereux MW, Orlicky DJ, Michel C, Petersen DR, Miller CG, Harpavat S, Schmidt EE, and Sokol RJ
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- Humans, Mice, Male, Animals, Aldehydes metabolism, Tandem Mass Spectrometry, Liver metabolism, Autophagy, Liver Cirrhosis pathology, Antioxidants metabolism, Cholestasis metabolism
- Abstract
Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in human and mouse cholestatic liver. Whereas mRNA expression of Atg12, Lamp1, Sqstm1 and Map1lc3 was increased in acute cholestasis in mice, it was either suppressed or not significantly changed in chronic cholestasis. In human and murine cholestasis, periportal hepatocytes showed increased IHC staining of ubiquitin, 4-HNE, p62, and selected antioxidant proteins. Increased p62 staining colocalized with accumulation of 4-HNE-modified proteins in periportal parenchymal cells as well as with periportal macrophages in both human and mouse liver. Mechanistically, p62 was identified as a direct target of lipid aldehyde adduction in PSC hepatic tissue and in vitro cell culture. In vitro LS-MS/MS analysis of 4-HNE treated recombinant p62 identified carbonylation of His123, Cys128, His174, His181, Lys238, Cys290, His340, Lys341 and His385. These data indicate that dysregulation of autophagy and oxidative stress/protein damage are present in the same periportal hepatocyte compartment of both human and murine cholestasis. Thus, our results suggest that both increased expression as well as ineffective autophagic degradation of oxidatively-modified proteins contributes to injury in periportal parenchymal cells and that direct modification of p62 by reactive aldehydes may contribute to autophagic dysfunction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Shearn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2022
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20. Rolling stones: an instructive case of neonatal cholestasis.
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Killelea P, Sakhuja S, Hernandez J, Hicks MJ, and Harpavat S
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- Humans, Hyperbilirubinemia diagnosis, Hyperbilirubinemia etiology, Infant, Infant, Newborn, Male, Ursodeoxycholic Acid therapeutic use, Biliary Atresia complications, Biliary Atresia diagnosis, Choledocholithiasis diagnosis, Choledocholithiasis diagnostic imaging, Cholestasis diagnosis, Cholestasis etiology, Infant, Newborn, Diseases, Jaundice, Neonatal complications, Jaundice, Neonatal etiology, Liver Diseases
- Abstract
Background: Jaundice within the first 1-2 weeks of a neonate's life will generally self-resolve; however, if it lasts longer than this time frame it warrants further work up. Direct or conjugated hyperbilirubinemia can suggest neonatal cholestasis, which in turn reflects marked reduction in bile secretion and flow. The differential diagnosis for neonatal cholestasis is broad. Neonatal choledocholithiasis is a rare cause of neonatal cholestasis, but should be considered on the differential diagnosis for patients presenting with elevated conjugated bilirubin., Case Presentation: We describe an infant who presented with neonatal cholestasis. He subsequently underwent work up for biliary atresia, as this is one of the more time-sensitive diagnoses that must be made in neonates with conjugated hyperbilirubinemia. He was ultimately found to have choledocholithiasis on magnetic resonance cholangiopancreatography. He was managed conservatively with optimizing nutrition and ursodeoxycholic acid therapy., Conclusions: We found that conservative management, specifically optimizing nutrition and treating with ursodeoxycholic acid, can be a sufficient approach to facilitating resolution of the choledocholithiasis and conjugated hyperbilirubinemia., (© 2022. The Author(s).)
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- 2022
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21. A Case Series of Children with Acute Hepatitis and Human Adenovirus Infection.
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Gutierrez Sanchez LH, Shiau H, Baker JM, Saaybi S, Buchfellner M, Britt W, Sanchez V, Potter JL, Ingram LA, Kelly D, Lu X, Ayers-Millsap S, Willeford WG, Rassaei N, Bhatnagar J, Bullock H, Reagan-Steiner S, Martin A, Rogers ME, Banc-Husu AM, Harpavat S, Leung DH, Moulton EA, Lamson DM, St George K, Hall AJ, Parashar U, MacNeil A, Tate JE, and Kirking HL
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- Acute Disease, Child, Child, Preschool, Humans, Infant, Viremia, Adenovirus Infections, Human complications, Adenovirus Infections, Human diagnosis, Adenovirus Infections, Human virology, Adenoviruses, Human genetics, Hepatitis virology
- Abstract
Background: Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia., Methods: We used International Classification of Diseases, 10th Revision , codes to identify all children (<18 years of age) with hepatitis who were admitted to Children's of Alabama hospital between October 1, 2021, and February 28, 2022; those with acute hepatitis who also tested positive for human adenovirus by whole-blood quantitative polymerase chain reaction (PCR) were included in our case series. Demographic, clinical, laboratory, and treatment data were obtained from medical records. Residual blood specimens were sent for diagnostic confirmation and human adenovirus typing., Results: A total of 15 children were identified with acute hepatitis - 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 additional patient referred to this facility for follow-up were included in this case series (median age, 2 years 11 months; age range, 1 year 1 month to 6 years 5 months). Liver biopsies indicated mild-to-moderate active hepatitis in 6 children, some with and some without cholestasis, but did not show evidence of human adenovirus on immunohistochemical examination or electron microscopy. PCR testing of liver tissue for human adenovirus was positive in 3 children (50%). Sequencing of specimens from 5 children showed three distinct human adenovirus type 41 hexon variants. Two children underwent liver transplantation; all the others recovered with supportive care., Conclusions: Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children's of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain. (Funded in part by the Centers for Disease Control and Prevention.)., (Copyright © 2022 Massachusetts Medical Society.)
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- 2022
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22. The Epidemiology of Biliary Atresia: Exploring the Role of Developmental Factors on Birth Prevalence.
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Cavallo L, Kovar EM, Aqul A, McLoughlin L, Mittal NK, Rodriguez-Baez N, Shneider BL, Zwiener RJ, Chambers TM, Langlois PH, Canfield MA, Agopian AJ, Lupo PJ, and Harpavat S
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- Female, Humans, Infant, Infant, Newborn, Live Birth, Pregnancy, Prevalence, Biliary Atresia epidemiology, Diabetes, Gestational, Premature Birth
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Objective: To identify key epidemiologic factors relevant to fetal development that are associated with biliary atresia., Study Design: This population-based registry study examined infants born in Texas between 1999 and 2014. Epidemiologic data relevant to fetal development were compared between cases of biliary atresia identified in the Texas Birth Defects Registry (n = 305) vs all live births (n = 4 689 920), and Poisson regression was used to calculate prevalence ratios (PRs) and 95% CIs., Results: The prevalence of biliary atresia over the study period was 0.65 per 10 000 live births. Biliary atresia was positively associated with female sex (adjusted PR, 1.68; 95% CI, 1.33-2.12), delivery before 32-37 weeks of gestation (adjusted PR, 1.64; 95% CI, 1.18-2.29), delivery before 32 weeks of gestation (adjusted PR, 3.85; 95% CI, 2.38-6.22), and non-Hispanic Black vs non-Hispanic White maternal race/ethnicity (adjusted PR, 1.54, 95% CI, 1.06-2.24), while biliary atresia was inversely associated with season of conception in the fall relative to spring (adjusted PR, 0.62; 95% CI, 0.45-0.86). In addition, biliary atresia was associated with maternal diabetes (adjusted PR, 2.34; 95% CI, 1.57-3.48), with a stronger association with pregestational diabetes compared with gestational diabetes. In subgroup analyses, these associations were present in isolated biliary atresia cases that do not have any additional birth defects., Conclusions: Biliary atresia is associated with multiple factors related to fetal development, including pregestational maternal diabetes, female sex, and preterm birth. These associations also were observed in isolated cases of biliary atresia without other malformations or laterality defects. Our results are consistent with early life events influencing the pathogenesis of biliary atresia, and support further studies investigating in utero events to better understand etiology and time of onset., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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23. Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement.
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de Ville de Goyet J, Illhardt T, Chardot C, Dike PN, Baumann U, Brandt K, Wildhaber BE, Pakarinen M, di Francesco F, Sturm E, Cornet M, Lemoine C, Pfister ED, Calinescu AM, Hukkinen M, Harpavat S, Tuzzolino F, and Superina R
- Abstract
Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016−2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population.
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- 2022
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24. Biliary Atresia in 2021: Epidemiology, Screening and Public Policy.
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Schreiber RA, Harpavat S, Hulscher JBF, and Wildhaber BE
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Biliary atresia (BA) is a rare newborn liver disease with significant morbidity and mortality, especially if not recognized and treated early in life. It is the most common cause of liver-related death in children and the leading indication for liver transplantation in the pediatric population. Timely intervention with a Kasai portoenterostomy (KPE) can significantly improve prognosis. Delayed disease recognition, late patient referral, and untimely surgery remains a worldwide problem. This article will focus on biliary atresia from a global public health perspective, including disease epidemiology, current national screening programs, and their impact on outcome, as well as new and novel BA screening initiatives. Policy challenges for the implementation of BA screening programs will also be discussed, highlighting examples from the North American, European, and Asian experience.
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- 2022
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25. The use of tracheostomy to support critically ill children receiving orthotopic liver transplantation: a single-center experience.
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Mian MUM, Kennedy C, Fogarty T 3rd, Naeem B, Lam F, Coss-Bu J, Arikan AA, Nguyen T, Bashir D, Virk M, Harpavat S, Raynor T, Rana AA, Goss J, Leung D, and Desai MS
- Subjects
- Adolescent, Child, Child, Preschool, Critical Illness, End Stage Liver Disease complications, End Stage Liver Disease mortality, Female, Humans, Infant, Infant, Newborn, Male, Multiple Organ Failure complications, Multiple Organ Failure mortality, Retrospective Studies, Survival Analysis, Treatment Outcome, Critical Care methods, End Stage Liver Disease surgery, Liver Transplantation, Multiple Organ Failure surgery, Perioperative Care methods, Tracheostomy
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Background: Children with end-stage liver disease and multi-organ failure, previously considered as poor surgical candidates, can now benefit from liver transplantation (LT). They often need prolonged mechanical ventilation (MV) post-LT and may need tracheostomy to advance care. Data on tracheostomy after pediatric LT are lacking., Method: Retrospective chart review of children who required tracheostomy in the peri-LT period in a large, freestanding quaternary children's hospital from 2014 to 2019., Results: Out of 205 total orthotopic LTs performed in 200 children, 18 (9%) required tracheostomy in the peri-transplant period: 4 (2%) pre-LT and 14 (7%) post-LT. Among those 14 needing tracheostomy post-LT, median age was 9 months [IQR = 7, 14] at LT and 10 months [9, 17] at tracheostomy. Nine (64%) were infants and 12 (85%) were cirrhotic at the time of LT. Seven (50%) were intubated before LT. Median MV days prior to LT was 23 [7, 36]. Eight (57%) patients received perioperative continuous renal replacement therapy (CRRT). The median MV days from LT to tracheostomy was 46 [33, 56]; total MV days from initial intubation to tracheostomy was 57 [37, 66]. Four (28%) children died, of which 3 (21%) died within 1 year of transplant. Total ICU and hospital length of stay were 92 days [I72, 126] and 177 days [115, 212] respectively. Among survivors, 3/10 (30%) required MV at home and 8/10 (80%) were successfully decannulated at 400 median days [283, 584]., Conclusion: Tracheostomy though rare after LT remains a feasible option to support and rehabilitate critically ill children who need prolonged MV in the peri-LT period., (© 2021 Wiley Periodicals LLC.)
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- 2022
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26. Newborn Screening for Biliary Atresia: a Review of Current Methods.
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Rabbani T, Guthery SL, Himes R, Shneider BL, and Harpavat S
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- Bile Acids and Salts, Humans, Infant, Newborn, Neonatal Screening, United States, Biliary Atresia diagnosis, Liver Transplantation
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Purpose of Review: Biliary atresia is a serious neonatal liver disease due to obstructed bile ducts that has better outcomes when detected and treated in the first 30-45 days of life. This review examines different methods to screen newborns for biliary atresia as well as discusses observations from ongoing screening programs implemented in parts of the United States., Recent Findings: Screening strategies for biliary atresia include detecting persistent jaundice, examining stool color, testing fractionated bilirubin levels, or measuring bile acid levels from dried blood spot cards. The stool color card program is the most widely used screening strategy worldwide. An alternative approach under investigation in the United States measures fractionated bilirubin levels, which are abnormal in newborns with biliary atresia. Fractionated bilirubin screening programs require laboratories to derive reference ranges, nurseries to implement universal testing, and healthcare systems to develop infrastructure that identifies and acts upon abnormal results. Biliary atresia meets the disease-specific criteria for newborn screening. Current studies focus on developing a strategy which also meets all test-specific criteria. Such a strategy, if implemented uniformly, has the potential to accelerate treatment and reduce biliary atresia's large liver transplant burden., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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27. Recent advances in the use of ultrasound and related techniques in diagnosing and predicting outcomes in biliary atresia.
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Dike PN, Mahmood N, and Harpavat S
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- Aged, Child, Humans, Infant, Liver, Ultrasonography, Biliary Atresia diagnostic imaging, Biliary Atresia surgery, Liver Transplantation
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Purpose of Review: Biliary atresia (BA) is the leading cause of chronic liver disease and the most common indication for pediatric liver transplantation. The use of ultrasound (US) and related techniques continues to evolve to help diagnose BA as well as potentially to help predict outcomes after treatment with the Kasai portoenterostomy (KP)., Recent Findings: There are no US findings that are definitive for BA; however, signs which are consistent with BA include gallbladder abnormalities, the triangular cord sign, presence of hepatic subcapsular flow, and hilar lymphadenopathy. Elastography techniques to measure liver stiffness may also increase the diagnostic accuracy of detecting BA, particularly in older infants or without other US findings. In addition, both US and elastography are still being studied as potential methods to predict outcomes after KP such as the development of portal hypertension and the need for liver transplant., Summary: US findings in the diagnosis of BA are well characterized. Future studies will help determine the utility of elastography in diagnosing BA, as well as both US and elastography in monitoring and predicting disease outcomes after KP., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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28. Operational Definitions for Chronic Liver Disease Manifestations and Recurring Clinical Events in Biliary Atresia.
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Shiau H, Schraw JM, Cavallo L, Leung DH, Harpavat S, Lupo PJ, and Shneider BL
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- Child, Female, Humans, Infant, Male, Portoenterostomy, Hepatic, Retrospective Studies, Treatment Outcome, Biliary Atresia complications, Biliary Atresia diagnosis, Biliary Atresia surgery, Hypertension, Portal
- Abstract
Background: The disease course of biliary atresia (BA) may be complicated by development of chronic liver disease (CLD) manifestations (eg, ascites) and recurring clinical events (eg, cholangitis). Most pediatric CLD-manifestations/events lack standardized operational definitions, leading to inconsistent identification in clinical research. This study aimed to develop operational research definitions of CLD-manifestations/events in BA for application in retrospective analysis., Methods: Operational definitions of CLD-manifestations/events were developed by literature review and revised by a panel of experienced pediatric hepatologists. Definitions were applied to a single-center review of infants with BA post-Kasai. Manifestations/events were captured until last clinical visit with native liver (SNL), liver transplantation (LT), or death. Native liver survival and event-free survival were estimated by Kaplan-Meier method. Cluster analysis was performed to identify similar patterns of manifestation/event development., Results: Of 65 infants with BA post-Kasai (2006-18; median Kasai 56.8 days; 65% girls), 29 underwent LT (median 12.9 months) and 4 died without LT (median 6.9 months). Seventy-six percent of CLD-manifestations/events presented within the first year. Presence of definite clinically evident portal hypertension, thrombocytopenia, and dCE ascites were associated with poor transplant-free survival (P < 0.01). Similar pattern developments of CLD-manifestations/events identified 3 outcome groups: poor outcomes (87.8% LT/death), SNL with manifestations/events, and SNL with few/no events., Conclusions: Operational definitions can provide a timely description of the disease course progression in infants with BA. Research definitions may provide better consistency in future pediatric CLD studies. Furthermore, definitions may serve as endpoints in therapeutic trials or used as variables for disease pattern identification in potential multicenter studies., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
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- 2021
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29. Use of Dietary Supplements in Pediatric Liver Disease and Transplantation.
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Korotkaya Y, Conner K, Lau J, Mullin G, Harpavat S, Miloh T, and Mogul D
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- Adolescent, Caregivers, Child, Humans, Parents, Dietary Supplements, Liver Diseases
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Background: Dietary supplements are frequently used by healthy individuals and those with chronic medical conditions but may cause damage to the liver. The aim of this study was to examine the prevalence and attitudes of dietary supplement use, and the frequency of disclosure to healthcare providers among parents/caregivers for children with chronic liver disease., Methods: We developed an anonymous survey for parents/caregivers of children (<18 years old) with chronic liver disease or liver transplant recipients and distributed the survey through social media groups organized around pediatric liver diseases., Results: The survey was completed by 101 parents/caregivers (48 without transplant and 53 posttransplant).Among respondents, 87% agreed they would use dietary supplements to help their child, but parents/caregivers of transplant recipients were less likely to consider use (77% vs 98%; P = 0.01). In the past 12 months, 83% reported dietary supplement use including 47% who used nonvitamin/mineral supplements. In two-thirds of parents/caregivers, use was initiated by their personal belief. Although 77% of respondents disclosed their use to their liver team, disclosure varied depending on the supplement with no individual that used cannabinoid products disclosing the use., Conclusions: Dietary supplements are frequently used by children with liver disease and may exceed use in other pediatric conditions. Though most parents report use to their liver team, disclosure may vary depending on the specific supplement. Providers should take extra measures to review use of supplements with their patients and work to develop trust with their families to obtain accurate disclosure of use., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
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- 2021
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30. Role for Social Media in Pediatric Liver Disease: Caregiver and Provider Perspectives.
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Mogul DB, Bowring MG, Lau J, Babin E, Bridges JFP, Harpavat S, and Miloh T
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Purpose: To better understand the benefits and harms of engagement with online pediatric liver disease communities within social media., Methods: We conducted a survey of caregivers of children with liver disease participating in online pediatric liver disease communities within social media, as well as a survey of healthcare providers (e.g., physicians, surgeons, nurse coordinators) from this field to better understand the perceived benefits and harms of participation., Results: Among 138 caregivers of children with liver disease that completed the survey, 97.8% agreed social media was a good place to learn about patient experiences and 88% agreed it was a good source of general information. Among caregivers, 84.8% agreed social media helps them to better advocate for their child. While 18% agreed that the information over social media was equal to the information from their healthcare team and 19% neither agreed/disagreed, only 3% indicated they would use this information to change care without telling their provider; in contrast, among 217 healthcare providers, 55% believed social media may lead caregivers to change management without telling their team., Conclusion: Engagement with online disease-specific communities in social media yields several benefits for caregivers and, in contrast to healthcare providers' concerns, participation is unlikely to lead to problems including caregivers changing the treatment plan without first discussing these plans with their team. Openness between caregivers and medical teams about the role for social media can help to improve trust and maximize the potential benefits of engagement with these groups., Competing Interests: Conflict of Interest: The authors report no conflict of interest., (Copyright © 2020 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)
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- 2020
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31. Modeling Outcomes in Children With Biliary Atresia With Native Liver After 2 Years of Age.
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Venkat V, 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, and Karpen SJ
- Abstract
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% (95% confidence interval [CI], 16.2%-32.0%). 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% (95% CI, 14.2%-29.8%) 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 (range, 0.80-0.84). Internal model validity was assessed using Harrell's C-index with cross-validation. Conclusion: 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., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)
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- 2020
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32. Transcriptomic analysis across liver diseases reveals disease-modulating activation of constitutive androstane receptor in cholestasis.
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Mathur B, Arif W, Patton ME, Faiyaz R, Liu J, Yeh J, Harpavat S, Schoonjans K, Kalsotra A, Wheatley AM, and Anakk S
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Background & Aims: Liver diseases are caused by many factors, such as genetics, nutrition, and viruses. Therefore, it is important to delineate transcriptomic changes that occur in various liver diseases., Methods: We performed high-throughput sequencing of mouse livers with diverse types of injuries, including cholestasis, diet-induced steatosis, and partial hepatectomy. Comparative analysis of liver transcriptome from mice and human samples of viral infections (HBV and HCV), alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH), and biliary atresia revealed distinct and overlapping gene profiles associated with liver diseases. We hypothesised that discrete molecular signatures could be utilised to assess therapeutic outcomes. We focused on cholestasis to test and validate the hypothesis using pharmacological approaches., Results: Here, we report significant overlap in the expression of inflammatory and proliferation-related genes across liver diseases. However, cholestatic livers were unique and displayed robust induction of genes involved in drug metabolism. Consistently, we found that constitutive androstane receptor (CAR) activation is crucial for the induction of the drug metabolic gene programme in cholestasis. When challenged, cholestatic mice were protected against zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. These protective effects were diminished upon inhibition of CAR activity. Further, drug metabolic genes were also induced in the livers from a subset of biliary atresia patients, but not in HBV and HCV infections, AH, or NASH. We also found a higher expression of CYP2B6, a CAR target, in the livers of biliary atresia patients, underscoring the clinical importance of our findings., Conclusions: Comparative transcriptome analysis of different liver disorders revealed specific induction of phase I and II metabolic genes in cholestasis. Our results demonstrate that CAR activation may lead to variations in drug metabolism and clinical outcomes in biliary atresia., Lay Summary: Transcriptomic analysis of diverse liver diseases revealed alterations in common and distinct pathways. Specifically, in cholestasis, we found that detoxification genes and their activity are increased. Thus, cholestatic patients may have an unintended consequence on drug metabolism and not only have a beneficial effect against liver toxicity, but also may require adjustments to their therapeutic dosage., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)
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- 2020
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33. Biliary Atresia Patients With Successful Kasai Portoenterostomy Can Present With Features of Obliterative Portal Venopathy.
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Patel KR, Harpavat S, Khan Z, Dhingra S, Quintanilla N, Firan M, and Goss J
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- Humans, Infant, Portoenterostomy, Hepatic, Biliary Atresia complications, Biliary Atresia surgery, Hypertension, Portal etiology, Hypertension, Portal surgery, Liver Transplantation
- Abstract
Objective: Study of liver explants of biliary atresia (BA) patients with successful Kasai portoenterostomy (KP)., Methods: Pathology and medical records of BA liver explants from January 2009 to June 2018 with successful KP were reviewed along with appropriate controls., Results: Fourteen out of 68 (20.6%) BA patients with LT had a successful KP. Median age at BA diagnosis, KP and LT was 60.5 days, 61 days, and 10 years, respectively, with conjugated bilirubin (c-bil) normalizing at 12.5 weeks after KP. Advanced fibrosis was diffuse in 2/14 (14.3%) explants, limited to periphery in 11/14 (78.6%) and absent in 1. Hilar partial nodular transformation (PNT) was seen in 11 explants (78.6%) and diffuse nodular regenerative hyperplasia (NRH) in 2 (14.3%). Areas of PNT and NRH showed diffuse portal sclerosis (100%), complete and incomplete portal vein (PV) stenosis (100%), PV herniation (100%), hypervascular portal tracts (20%), periportal abnormal vessels (100%), abundant lymphatic collaterals (100%), mild medial hepatic arterial hypertrophy (100%), and delicate fibrous septae (100%). Extrahepatic PVs showed variable luminal occlusion with mean PV intima to full thickness ratio of 0.6 +/- 0.11; significantly higher than age-matched noncirrhotic (n = 27, 0.08 +/- 0.09; P < 0.0001) and cirrhotic controls (n = 19, 0.34 +/- 0.2; P = 0.0015); and comparable to BA patients with failed KP (P = 0.82) and without KP (P = 0.04)., Conclusions: BA patients with successful KP can present with obliterative portal venopathy (OPV). In the context of optimal bile drainage, portal hypertension may not be because of advanced parenchymal fibrosis but possibly because of OPV. Vascular abnormalities of the PV system should be investigated in BA patients.
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- 2020
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34. The Fecal Microbiome in Infants With Biliary Atresia Associates With Bile Flow After Kasai Portoenterostomy.
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Tessier MEM, Cavallo L, Yeh J, Harpavat S, Hoffman KL, Petrosino JF, and Shneider BL
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- Bile, Humans, Infant, Portoenterostomy, Hepatic, Biliary Atresia surgery, Liver Transplantation, Microbiota
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Background: Biliary atresia's (BA) response to surgical Kasai portoenterostomy (KP) is uneven and dependent upon bile flow; 50% of infants require a liver transplant by 24 months. We hypothesized that the microbiome may identify and associate with outcomes in BA., Methods: Stool samples were collected from infants with cholestasis (n = 15), 8 of which with BA were followed longitudinally.16S sequencing was performed on all samples (n = 45). Whole Genome Sequencing (WGS) was performed on BA pre-KP samples (n = 8). Infants with BA, other forms of cholestasis, BA infants with very good bile flow (VGBF) and not (nVGBF) (VGBF dichotomized by TSBA <40 μmol/L by 6 months) were compared., Results: Of the 8 infants with BA, 4 infants had VGBF. Microbial richness was inversely proportional to degree of cholestasis (P = 0.046). Increased Bifidobacterium abundance associated with VGBF (P = 0.03) and decreased cholestasis (P < 0.01) at 1 month post-KP. Pre-KP, community structure differed in infants with BA versus other cholestasis. Interestingly, infants who subsequently achieved VGBF had increased diversity (P = 0.03) and different community structure at the pre-KP time point. WGS corroborated Bifidobacterium's pre-KP importance., Conclusions: The microbiome differs between infants with BA and other cholestasis. It additionally differs between infants with BA who have good and poor bile flow, and thus outcomes, post-KP. These differences are seen even before KP. These data suggest that bile influences the development of the infant microbiome and that there may be possible influences of the pre- and post-KP microbiome on bile flow after KP. Further larger studies are needed to confirm these findings.
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- 2020
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35. Response to Letter: If Biliary Atresia Is a Disease Starting In Utero: Should We Treat Ongoing Cytomegalovirus.
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Mysore KR, Shneider BL, and Harpavat S
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- Cytomegalovirus, Humans, Longitudinal Studies, Portoenterostomy, Hepatic, Biliary Atresia surgery, Cytomegalovirus Infections
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- 2020
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36. Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements.
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Harpavat S, Garcia-Prats JA, Anaya C, Brandt ML, Lupo PJ, Finegold MJ, Obuobi A, ElHennawy AA, Jarriel WS, and Shneider BL
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- Age Factors, Biliary Atresia blood, Biliary Atresia surgery, Cross-Sectional Studies, Female, Humans, Infant, Infant, Newborn, Liver Transplantation, Male, Predictive Value of Tests, Reference Values, Sensitivity and Specificity, Time-to-Treatment, Biliary Atresia diagnosis, Bilirubin blood, Neonatal Screening methods, Portoenterostomy, Hepatic statistics & numerical data
- Abstract
Importance: Treating biliary atresia in newborns earlier can delay or prevent the need for liver transplant; however, treatment typically occurs later because biliary atresia is difficult to detect during its early stages., Objective: To determine the diagnostic yield of newborn screening for biliary atresia with direct or conjugated bilirubin measurements and to evaluate the association of screening implementation with clinical outcomes., Design, Setting, and Participants: A cross-sectional screening study of 124 385 infants born at 14 Texas hospitals between January 2015 and June 2018; and a pre-post study of 43 infants who underwent the Kasai portoenterostomy as treatment for biliary atresia at the region's largest pediatric hepatology center before (January 2008-June 2011) or after (January 2015-June 2018) screening implementation. Final follow-up occurred on July 15, 2019., Exposures: Two-stage screening with direct or conjugated bilirubin measurements. In stage 1, all newborns were tested within the first 60 hours of life, with a positive screening result defined as bilirubin levels exceeding derived 95th percentile reference intervals. In stage 2, infants who had a positive screening result in stage 1 were retested at or before the 2-week well-child visit, with a positive screening result defined as bilirubin levels greater than the stage 1 result or greater than 1 mg/dL., Main Outcomes and Measures: The primary outcomes of the screening study were sensitivity, specificity, positive predictive value, and negative predictive value based on infants testing positive in both stages. The reference standard was biliary atresia diagnosed at the region's pediatric hepatology centers. The primary outcome of the pre-post study was the age infants underwent the Kasai portoenterostomy for treatment of biliary atresia., Results: Of 124 385 newborns in the screening study, 49.2% were female, 87.6% were of term gestational age, 70.0% were white, and 48.1% were Hispanic. Screening identified the 7 known infants with biliary atresia with a sensitivity of 100% (95% CI, 56.1%-100.0%), a specificity of 99.9% (95% CI, 99.9%-99.9%), a positive predictive value of 5.9% (95% CI, 2.6%-12.2%), and a negative predictive value of 100.0% (95% CI, 100.0%-100.0%). In the pre-post study, 24 infants were treated before screening implementation and 19 infants were treated after screening implementation (including 6 of 7 from the screening study, 7 from screening at nonstudy hospitals, and 6 from referrals because of clinical symptoms). The age infants underwent the Kasai portoenterostomy was significantly younger after screening was implemented (mean age, 56 days [SD, 19 days] before screening implementation vs 36 days [SD, 22 days] after screening implementation; between-group difference, 19 days [95% CI, 7-32 days]; P = .004)., Conclusions and Relevance: Newborn screening with direct or conjugated bilirubin measurements detected all known infants with biliary atresia in the study population, although the 95% CI around the sensitivity estimate was wide and the study design did not ensure complete ascertainment of false-negative results. Research is needed in larger populations to obtain more precise estimates of diagnostic yield and to better understand the clinical outcomes and cost-effectiveness of this screening approach.
- Published
- 2020
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37. Commentary.
- Author
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Edwards PT and Harpavat S
- Subjects
- Humans, Infant, Newborn, Fractures, Multiple, Jaundice
- Published
- 2019
- Full Text
- View/download PDF
38. Biliary Atresia as a Disease Starting In Utero: Implications for Treatment, Diagnosis, and Pathogenesis.
- Author
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Mysore KR, Shneider BL, and Harpavat S
- Subjects
- Adult, Female, Humans, Infant, Newborn, Pregnancy, Biliary Atresia diagnosis, Neonatal Screening, Prenatal Diagnosis
- Abstract
Biliary atresia (BA) is the most common reason for pediatric liver transplant. BA's varied presentation, natural history, and treatment with the Kasai portoenterostomy have been well described; however, when BA starts relative to birth has not been clearly defined. In this review, we discuss laboratory, imaging, and clinical data which suggest that most if not all forms of BA may start before birth. This early onset has implications in terms of delivering treatments earlier and identifying possible factors underlying BA's etiology.
- Published
- 2019
- Full Text
- View/download PDF
39. Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome.
- Author
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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 NB, 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, and Karpen SJ
- Subjects
- Abnormalities, Multiple pathology, Biliary Atresia pathology, Child, Databases, Factual, Female, Gene Expression Regulation, Developmental, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Polycystic Kidney Diseases pathology, Retrospective Studies, Syndrome, Exome Sequencing, Abnormalities, Multiple genetics, Biliary Atresia genetics, Membrane Proteins genetics, Polycystic Kidney Diseases genetics, Spleen abnormalities
- Abstract
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., (© 2019 by the American Association for the Study of Liver Diseases.)
- Published
- 2019
- Full Text
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40. A phase 2 trial of N-Acetylcysteine in Biliary atresia after Kasai portoenterostomy.
- Author
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Tessier MEM, Shneider BL, Brandt ML, Cerminara DN, and Harpavat S
- Abstract
Background: Biliary atresia (BA) is a life-threatening liver disease of infancy, characterized by extrahepatic biliary obstruction, bile retention, and progressive liver injury. The Kasai portoenterostomy (KP) is BA's only nontransplant treatment. Its success is variable and depends on restoration of hepatic bile flow. Many adjunctive therapeutics have been studied to improve outcomes after the KP, but none demonstrate effectiveness. This study tests if N-acetylcysteine (NAC), a precursor to the choleretic glutathione, improves bile flow after KP., Methods: This report describes the design of an open-label, single center, Phase 2 study to determine the effect of NAC following KP on markers of bile flow and outcomes in BA. The intervention is intravenous NAC (150 mg/kg/day) administered continuously for seven days starting 0-24 h after KP. The primary outcome is normalization of total serum bile acid (TSBA) concentrations within 24 weeks of KP. The secondary objectives are to describe NAC therapy's effect on other clinical parameters followed in BA for 24 months and to report adverse events occurring with therapy. This study follows the "minimax" clinical trial design., Discussion: This is the first clinical trial to test NAC's effectiveness in improving bile flow after KP in BA. It introduces three important concepts for future BA therapeutic trials: (1) the "minimax" study design, a pertinent design for rare diseases because it detects potential effects quickly with small subject size; (2) the more sensitive bile flow marker, TSBAs, which may correlate with positive long-term outcomes better than traditional bile flow markers such as serum bilirubin; and (3) liver enzyme changes immediately after KP, which can be a guideline for potential drug-induced liver injury in other BA peri-operative adjunctive therapeutic trials.
- Published
- 2019
- Full Text
- View/download PDF
41. MMP-7: The Next Best Serum Biomarker for Biliary Atresia?
- Author
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Harpavat S
- Subjects
- Biomarkers, Humans, Matrix Metalloproteinase 7, Portoenterostomy, Hepatic, Biliary Atresia surgery, Liver Transplantation
- Published
- 2019
- Full Text
- View/download PDF
42. Factors Influencing Time-to-diagnosis of Biliary Atresia.
- Author
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Harpavat S, Lupo PJ, Liwanag L, Hollier J, Brandt ML, Finegold MJ, and Shneider BL
- Subjects
- Biliary Atresia surgery, Female, Humans, Infant, Infant, Newborn, Kaplan-Meier Estimate, Liver Transplantation, Male, Neonatal Screening, Portoenterostomy, Hepatic, Proportional Hazards Models, Referral and Consultation, Retrospective Studies, Time Factors, Biliary Atresia diagnosis, Delayed Diagnosis statistics & numerical data, Early Diagnosis
- Abstract
Objectives: Diagnosing biliary atresia (BA) quickly is critical, because earlier treatment correlates with delayed or reduced need for liver transplantation. However, diagnosing BA quickly is also difficult, with infants usually treated after 60 days of life. In this study, we aim to accelerate BA diagnosis and treatment, by better understanding factors influencing the diagnostic timeline., Methods: Infants born between 2007 and 2014 and diagnosed with BA at our institution were included (n = 65). Two periods were examined retrospectively: P1, the time from birth to specialist referral, and P2, the time from specialist referral to treatment. How sociodemographic factors associate with P1 and P2 were analyzed with Kaplan-Meier curves and Cox proportional hazard models. In addition, to better characterize P2, laboratory results and early tissue histology were studied., Results: P1 associated with race/ethnicity, with shorter times in non-Hispanic white infants compared to non-Hispanic black and Hispanic infants (P = 0.007 and P = 0.004, respectively). P2 associated with referral age, with shorter times in infants referred after 30, 45, or 60 days of life (P < 0.001, P < 0.001, and P = 0.001, respectively). One potential reason for longer P2 in infants referred ≤30 days is that aminotransferase levels were normal or near-normal. However, despite reassuring laboratory values, tissue histology in early cases showed key features of BA., Conclusions: Our findings suggest 2 opportunities to accelerate BA diagnosis and treatment. First, to achieve prompt referrals for all races/ethnicities, universal screening strategies should be considered. Second, to ensure efficient evaluations independent of age, algorithms designed to detect early features of BA can be developed.
- Published
- 2018
- Full Text
- View/download PDF
43. Population-based birth defects data in the United States, 2010-2014: A focus on gastrointestinal defects.
- Author
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Lupo PJ, Isenburg JL, Salemi JL, Mai CT, Liberman RF, Canfield MA, Copeland G, Haight S, Harpavat S, Hoyt AT, Moore CA, Nembhard WN, Nguyen HN, Rutkowski RE, Steele A, Alverson CJ, Stallings EB, and Kirby RS
- Subjects
- Biliary Atresia epidemiology, Colon abnormalities, Databases, Factual, Esophageal Atresia epidemiology, Female, Gastrointestinal Tract, Humans, Intestinal Atresia epidemiology, Live Birth, Male, Population Surveillance methods, Pregnancy, Prevalence, Registries, Tracheoesophageal Fistula epidemiology, United States, Congenital Abnormalities epidemiology, Gastrointestinal Diseases epidemiology
- Abstract
Background: Gastrointestinal defects are a phenotypically and etiologically diverse group of malformations. Despite their combined prevalence and clinical impact, little is known about the epidemiology of these birth defects. Therefore, the objective of the 2017 National Birth Defects Prevention Network (NBDPN) data brief was to better describe the occurrence of gastrointestinal defects., Methods: As part of the 2017 NBDPN annual report, 28 state programs provided additional data on gastrointestinal defects for the period 2010-2014. Counts and prevalence estimates (per 10,000 live births) were calculated overall and by demographic characteristics for (1) biliary atresia; (2) esophageal atresia/tracheoesophageal fistula; (3) rectal and large intestinal atresia/stenosis; and (4) small intestinal atresia/stenosis. Additionally, we explored the frequency of these malformations co-occurring with other structural birth defects., Results: Pooling data from all participating registries, the prevalence estimates were: 0.7 per 10,000 live births for biliary atresia (713 cases); 2.3 per 10,000 live births for esophageal atresia/tracheoesophageal fistula (2,472 cases); 4.2 per 10,000 live births for rectal and large intestinal atresia/stenosis (4,334 cases); and 3.4 per 10,000 live births for small intestinal atresia/stenosis (3,388 cases). Findings related to co-occurring birth defects were especially notable for esophageal atresia/tracheoesophageal fistula, rectal and large intestinal atresia/stenosis, and small intestinal atresia/stenosis, where the median percentage of non-isolated cases was 53.9%, 45.5%, and 50.6%, respectively., Conclusions: These population-based prevalence estimates confirm some previous studies, and provide a foundation for future epidemiologic studies of gastrointestinal defects. Exploring the genetic and environmental determinants of these malformations may yield new clues into their etiologies., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
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44. Post-transplant Recurrent Bile Salt Export Pump Disease: A Form of Antibody-mediated Graft Dysfunction and Utilization of C4d.
- Author
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Patel KR, Harpavat S, Finegold M, Eldin K, Hicks J, Firan M, Keitel V, Kubitz R, and Wu H
- Subjects
- Cholestasis, Intrahepatic drug therapy, Cholestasis, Intrahepatic metabolism, Female, Humans, Immunohistochemistry, Infant, Rituximab therapeutic use, ATP Binding Cassette Transporter, Subfamily B, Member 11 metabolism, Cholestasis, Intrahepatic diagnosis, Graft Rejection immunology, Liver pathology, Liver Transplantation adverse effects
- Abstract
Recurrent bile salt export pump (rBSEP) disease has been reported in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients following liver transplantation (LT) and is often refractory to standard anti-cellular rejection immunosuppressants. The mechanism of rBSEP disease is proposed to be a form of type II hypersensitivity reaction with de novo anti-BSEP antibodies blocking the function of allograft BSEP. Utilization of C4d has not been evaluated in rBSEP. We describe a girl with 3 episodes of rBSEP with severe pruritus at 8.9, 10.3, and 11.0 years post-LT, respectively. Patient's serum reacted with normal liver canaliculi by indirect immunofluorescence (IF), whereas patient's liver showed canalicular immunoglobulin G deposition. The histologic features of all 3 liver biopsies recapitulate PFIC2 with cholestatic giant cell hepatitis. Canalicular BSEP expression was not detected in areas of feathery degeneration by immunohistochemistry, but was retained in morphologically normal liver. By direct IF, C4d showed diffuse sinusoidal staining in the third biopsy. Patient responded well to rituximab with or without intravenous immunoglobulin with subsiding symptoms and normalization of serum bile acid levels. In conclusion, rBSEP disease should be considered in the differential diagnosis when evaluating for rejection in a PFIC2 patient post-LT presenting with pruritus. A portion of liver core may be snap frozen in OCT medium for possible direct IF for C4d, that can serve as a surrogate marker for complement activation and antibody-mediated graft dysfunction.
- Published
- 2017
- Full Text
- View/download PDF
45. Level of γ-glutamyltransferase in 2-Year-old Children With Biliary Atresia Associates With Progression of Portal Hypertension.
- Author
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Freeman AJ, Ng VL, Harpavat S, Hrycko A, Apted Z, Bulut P, Leong T, and Karpen SJ
- Subjects
- Biomarkers blood, Child, Preschool, Disease Progression, Humans, Hypertension, Portal enzymology, Retrospective Studies, Thrombocytopenia enzymology, Biliary Atresia enzymology, Hypertension, Portal etiology, Thrombocytopenia etiology, gamma-Glutamyltransferase blood
- Published
- 2017
- Full Text
- View/download PDF
46. Newborn Bilirubin Screening for Biliary Atresia.
- Author
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Harpavat S, Garcia-Prats JA, and Shneider BL
- Subjects
- Biliary Atresia blood, Humans, Infant, Newborn, Predictive Value of Tests, Sensitivity and Specificity, Biliary Atresia diagnosis, Bilirubin blood, Neonatal Screening
- Published
- 2016
- Full Text
- View/download PDF
47. Glucocorticoids Have Opposing Effects on Liver Fibrosis in Hepatic Stellate and Immune Cells.
- Author
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Kim KH, Lee JM, Zhou Y, Harpavat S, and Moore DD
- Subjects
- Animals, Carbon Tetrachloride toxicity, Cell Line, Cells, Cultured, Chemical and Drug Induced Liver Injury drug therapy, Chemical and Drug Induced Liver Injury metabolism, Humans, Immunohistochemistry, Liver cytology, Liver drug effects, Liver injuries, Liver metabolism, Lymphocytes drug effects, Lymphocytes metabolism, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes drug effects, Monocytes metabolism, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Signal Transduction drug effects, Glucocorticoids therapeutic use, Hepatic Stellate Cells drug effects, Hepatic Stellate Cells metabolism, Liver Cirrhosis drug therapy, Liver Cirrhosis metabolism
- Abstract
Liver fibrosis is a reversible wound-healing process that is protective in the short term, but prolonged fibrotic responses lead to excessive accumulation of extracellular matrix components that suppresses hepatocyte regeneration, resulting in permanent liver damage. Upon liver damage, nonparenchymal cells including immune cells and hepatic stellate cells (HSCs) have crucial roles in the progression and regression of liver fibrosis. Here, we report differential roles of the glucocorticoid receptor (GR), acting in immune cells and HSCs, in liver fibrosis. In the carbon tetrachloride hepatotoxin-induced fibrosis model, both steroidal and nonsteroidal GR ligands suppressed expression of fibrotic genes and decreased extracellular matrix deposition but also inhibited immune cell infiltration and exacerbated liver injury. These counteracting effects of GR ligands were dissociated in mice with conditional GR knockout in immune cells (GR(LysM)) or HSC (GR(hGFAP)): the impacts of dexamethasone on immune cell infiltration and liver injury were totally blunted in GR(LysM) mice, whereas the suppression of fibrotic gene expression was diminished in GR(hGFAP) mice. The effect of GR activation in HSC was further confirmed in the LX-2 HSC cell line, in which antifibrotic effects were mediated by GR ligand inhibition of Sma and mad-related protein 3 (SMAD3) expression. We conclude that GR has differential roles in immune cells and HSCs to modulate liver injury and liver fibrosis. Specific activation of HSC-GR without alteration of GR activity in immune cells provides a potential therapeutic approach to treatment of hepatic fibrosis.
- Published
- 2016
- Full Text
- View/download PDF
48. Newborn Direct or Conjugated Bilirubin Measurements As a Potential Screen for Biliary Atresia.
- Author
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Harpavat S, Ramraj R, Finegold MJ, Brandt ML, Hertel PM, Fallon SC, Shepherd RW, and Shneider BL
- Subjects
- Female, Humans, Infant, Infant, Newborn, Male, Retrospective Studies, Sensitivity and Specificity, Biliary Atresia diagnosis, Bilirubin blood, Neonatal Screening methods
- Abstract
Objectives: Although screening for biliary atresia (BA) is associated with improved outcomes, no screening program currently exists in the United States. In this study, we explore the possibility of a screening strategy based on newborn direct or conjugated bilirubin (DB or CB) measurements. Our objective is to estimate testing's sensitivity and specificity for BA., Methods: Two groups were examined retrospectively. For sensitivity calculations, a BA group consisting of infants born between January 2011 and December 2014, diagnosed with BA, and cared for at a pediatric gastroenterology referral center was examined. For specificity calculations, a non-BA group that comprised of infants born between June 2009 and August 2011 in a hospital with a policy of checking newborn bilirubin concentrations was studied., Results: All 35 infants with newborn DB or CB measurements in the BA group had elevated concentrations, translating to a sensitivity of 100% (95% CI 87.7-100). In the non-BA group, 8936 of 9102 infants had DB concentrations within the laboratory's reference interval, translating to a specificity of 98.2% (95% CI 97.9-98.4). Three methods-calculating direct:total bilirubin ratios, using 99% reference intervals, and repeat testing-changed specificity to different degrees., Conclusions: Newborn DB or CB measurements may have a high sensitivity and specificity for BA. Specificity can be further improved by using 99% reference intervals and/or repeat testing. Our findings can serve as the foundation for larger prospective studies, to determine whether newborn DB or CB measurements can be an effective screening strategy for BA.
- Published
- 2016
- Full Text
- View/download PDF
49. Drug-induced liver injury in children.
- Author
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Amin MD, Harpavat S, and Leung DH
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal adverse effects, Chemical and Drug Induced Liver Injury prevention & control, Chemical and Drug Induced Liver Injury surgery, Child, Child, Preschool, Enzyme Inhibitors adverse effects, Fluoroquinolones adverse effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Risk Factors, United States epidemiology, Chemical and Drug Induced Liver Injury epidemiology, Liver pathology, Liver Transplantation
- Abstract
Purpose of Review: Drug-induced liver injury (DILI) is an underrecognized cause of pediatric liver disease, accounts for almost 20% of pediatric acute liver failure cases, and is a major reason for liver transplantation in the USA. This article reviews the pathogenesis of DILI, approach to diagnosis and management, and highlights recent pediatric DILI case series., Recent Findings: Select individuals have an increased propensity to develop DILI. Known genetic polymorphisms of enzymes and host factors play an important role in medication management and influence the clinical outcome in 20-25% of all drug therapies. Children are more likely to have mitochondrial dysfunction from drugs, increasing their susceptibility to severe liver injury or acute liver failure. Antibiotics and central nervous system agents account for the majority of pediatric DILI in the West, although herbals are becoming more common., Summary: Clinical features of DILI vary and overlap so exclusion of other conditions, identification of latency period and risk factors, and use of a searchable database can aid evaluation. Treatment consists of cessation of the offending agent and supportive care. Areas needing further research include elucidating mechanisms, identifying at risk individuals, and therapeutic interventions.
- Published
- 2015
- Full Text
- View/download PDF
50. An infant with persistent jaundice and a normal newborn direct bilirubin measurement.
- Author
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Harpavat S, Devaraj S, and Finegold MJ
- Subjects
- Biliary Atresia blood, Biliary Atresia complications, Biliary Atresia diagnosis, Bilirubin analysis, Humans, Infant, Jaundice complications, Liver pathology, Liver Diseases blood, Liver Diseases diagnosis, Bilirubin blood, Jaundice blood, Jaundice diagnosis
- Published
- 2015
- Full Text
- View/download PDF
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