Pub Date : 2019-06-07DOI: 10.1097/MPG.0000000000002414
S. Honigbaum, Qingfeng Zhu, Andrew J. Layman, R. Anders, K. Schwarz
Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be anti-fibrotic in animals. OBJECTIVES to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues. METHODS Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared to non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed. RESULTS Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 (p ≤ 0.001) for non-BA and distribution of bile duct staining score of 3.0 vs. 2.8 (p = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 vs 3.1 for non-BA. Non-hepatic pediatric tissue displayed minimal to no LOXL2 staining. CONCLUSIONS There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extra-hepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.
胆道闭锁(BA)的特征是胆道迅速进展的炎症和纤维化，尽管手术干预(Kasai肝肠口造口术)，但通常会进展。赖氨酸氧化酶样(LOXL2)是一种细胞外基质酶，催化纤维性胶原蛋白和弹性蛋白的交联，被认为在组织纤维化中起关键作用;抗loxl2药物已被证明在动物中具有抗纤维化作用。目的探讨BA肝及肝外对照组织中LOXL2的存在。方法在Kasai获得BA婴儿(n = 20)的银楔活检，并与非BA肝脏(n = 20)进行比较。使用Ishak量表对肝纤维化进行评分，使用市购的多克隆抗loxl2抗体进行免疫组化。由不知道诊断的病理学家对LOXL2的表达强度和胆管染色的分布进行评分。对儿童对照组织、肌肉(n = 5)、心脏(n = 5)和骨骼(n = 10)进行LOXL2染色。结果BA患者组织中LOXL2表达丰富(强度评分2.0 vs 1.4 (p≤0.001))，非BA患者组织中LOXL2分布染色评分3.0 vs 2.8 (p = 0.001)。所有BA样本的纤维化评分为4.2，非BA样本为3.1。非肝脏儿童组织显示很少或没有LOXL2染色。结论LOXL2在BA肝组织中过表达，而在肝外组织中表达较少。Kasai在人肝组织中的过表达提示了进一步研究抗loxl2治疗BA的基本原理。
{"title":"Abundant Expression of Lysyl Oxidase-Like 2 Protein in Intra-Hepatic Bile Ducts of Infants with Biliary Atresia.","authors":"S. Honigbaum, Qingfeng Zhu, Andrew J. Layman, R. Anders, K. Schwarz","doi":"10.1097/MPG.0000000000002414","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002414","url":null,"abstract":"Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be anti-fibrotic in animals.\u0000\u0000\u0000OBJECTIVES\u0000to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues.\u0000\u0000\u0000METHODS\u0000Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared to non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed.\u0000\u0000\u0000RESULTS\u0000Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 (p ≤ 0.001) for non-BA and distribution of bile duct staining score of 3.0 vs. 2.8 (p = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 vs 3.1 for non-BA. Non-hepatic pediatric tissue displayed minimal to no LOXL2 staining.\u0000\u0000\u0000CONCLUSIONS\u0000There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extra-hepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72546528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-05-28DOI: 10.1097/MPG.0000000000002411
E. Brenner, F. Sylvester
n this edition of the Journal of Pediatric Gastroenterology and Nutrition, Holmes et al (1) describe an association between I higher exposure to sunlight and decreased risk of pediatric inflammatory bowel disease (IBD), based on a matched case-control study. The authors delineate the strengths and limitations of their methodology, including the possibility of recall bias from estimating cumulative exposure to sunshine with a questionnaire. Nonetheless, this study may offer the best possible data to examine whether sunshine protects against IBD. The alternative, which is to follow a large group of children prospectively for many years to address this question, is highly impractical. So, should we let our children run in the sun to protect them from developing IBD? To answer this question, we would first like to discuss possible reasons for a protective effect of sun exposure on IBD risk. First, sunlight increases the cutaneous synthesis of vitamin D. Vitamin D may then decrease IBD risk. We discuss supportive evidence for this possibility in more detail below. Alternatively, sunshine may exert a vitamin D-unrelated effect on the skin that mitigates IBD risk. For example, ultraviolet radiation upregulates the expression of adrenocorticotropin hormone, which stimulates the synthesis of cortisol, a known immune modulator (2). Additionally, an activity or behavior performed outdoors, such as exercise, may protect from developing IBD. Along these lines, the Nurses’ Health Study found that exercise is associated with a decreased risk of developing Crohn disease (3). As well, higher exposure to sunlight may be a marker of a lifestyle that reduces the risk of IBD for reasons that are unrelated to sunshine per se, such as diet. Cutaneous vitamin D synthesis induced by ultraviolet radiation may decrease the risk of IBD via several possible mechanisms. For example, multiple in vitro studies have shown that vitamin D stimulates innate immune activity and dampens adaptive immune function (4). If the same occurs in vivo, vitamin D may decrease the likelihood of developing IBD by affecting the immune system. In mouse studies, vitamin D supplementation decreases the severity of dextran sodium sulfate (DSS)-induced colitis (5). Overexpression of human vitamin D receptor (hVDR) in mice reduces the severity of experimental colitis, possibly because of the reduction of intestinal epithelial cell apoptosis (6). VDR knockout mice develop severe gastrointestinal inflammation, suggesting a role for VDRmediated signaling in gastrointestinal immune function (7). In another
{"title":"To Prevent IBD in Children, Let the Sunshine in?","authors":"E. Brenner, F. Sylvester","doi":"10.1097/MPG.0000000000002411","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002411","url":null,"abstract":"n this edition of the Journal of Pediatric Gastroenterology and Nutrition, Holmes et al (1) describe an association between I higher exposure to sunlight and decreased risk of pediatric inflammatory bowel disease (IBD), based on a matched case-control study. The authors delineate the strengths and limitations of their methodology, including the possibility of recall bias from estimating cumulative exposure to sunshine with a questionnaire. Nonetheless, this study may offer the best possible data to examine whether sunshine protects against IBD. The alternative, which is to follow a large group of children prospectively for many years to address this question, is highly impractical. So, should we let our children run in the sun to protect them from developing IBD? To answer this question, we would first like to discuss possible reasons for a protective effect of sun exposure on IBD risk. First, sunlight increases the cutaneous synthesis of vitamin D. Vitamin D may then decrease IBD risk. We discuss supportive evidence for this possibility in more detail below. Alternatively, sunshine may exert a vitamin D-unrelated effect on the skin that mitigates IBD risk. For example, ultraviolet radiation upregulates the expression of adrenocorticotropin hormone, which stimulates the synthesis of cortisol, a known immune modulator (2). Additionally, an activity or behavior performed outdoors, such as exercise, may protect from developing IBD. Along these lines, the Nurses’ Health Study found that exercise is associated with a decreased risk of developing Crohn disease (3). As well, higher exposure to sunlight may be a marker of a lifestyle that reduces the risk of IBD for reasons that are unrelated to sunshine per se, such as diet. Cutaneous vitamin D synthesis induced by ultraviolet radiation may decrease the risk of IBD via several possible mechanisms. For example, multiple in vitro studies have shown that vitamin D stimulates innate immune activity and dampens adaptive immune function (4). If the same occurs in vivo, vitamin D may decrease the likelihood of developing IBD by affecting the immune system. In mouse studies, vitamin D supplementation decreases the severity of dextran sodium sulfate (DSS)-induced colitis (5). Overexpression of human vitamin D receptor (hVDR) in mice reduces the severity of experimental colitis, possibly because of the reduction of intestinal epithelial cell apoptosis (6). VDR knockout mice develop severe gastrointestinal inflammation, suggesting a role for VDRmediated signaling in gastrointestinal immune function (7). In another","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"35 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83518434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-05-18DOI: 10.1097/MPG.0000000000002396
A. Grant, M. Crane, A. Laupacis, A. Griffiths, D. Burnett, Amanda Hood, C. Kluthe, Muneet Maghera, Malcolm Mann, M. Mansi, Kate Murray, M. Trempe, A. Otley
INTRODUCTION Including individuals with lived experience in pediatric IBD is essential to establishing a research agenda that is mutually impactful to both those treating and those experiencing the disease. METHODS Using the James Lind Alliance approach to research priority setting, a 10-member steering committee comprised of current and former pediatric IBD patients, caregivers, and clinicians was formed. A national survey, disseminated across Canada, elicited uncertainties which were divided into unanswered and answered research questions. Subsequently a research prioritization survey was disseminated where respondents ranked their top 20 research uncertainties. A final prioritization meeting was held to agree upon the top 10 uncertainties. RESULTS From 1209 research questions submitted by 363 participants, the list was reduced to 105 indicative questions that were within scope and deemed unanswered in the literature. Via the national research prioritization survey, this list was further reduced. The top 10 uncertainties identified at the final research consensus meeting, with 21 participants from all stakeholder groups, included: "What are the causes of IBD?", "Can IBD be prevented?", "What role does diet have in the management of pediatric IBD?". Other questions concerned flare ups, biomarkers, optimal patient education, long-term effects of medication and early-diagnosis, role of psychological support, and optimal approach to diagnosis. CONCLUSION This research adds a unique perspective by deriving a list of pediatric IBD research uncertainties important by patients and caregivers, as well as clinicians.
{"title":"Engaging Patients and Caregivers in Research for Pediatric IBD: Top 10 Research Priorities.","authors":"A. Grant, M. Crane, A. Laupacis, A. Griffiths, D. Burnett, Amanda Hood, C. Kluthe, Muneet Maghera, Malcolm Mann, M. Mansi, Kate Murray, M. Trempe, A. Otley","doi":"10.1097/MPG.0000000000002396","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002396","url":null,"abstract":"INTRODUCTION\u0000Including individuals with lived experience in pediatric IBD is essential to establishing a research agenda that is mutually impactful to both those treating and those experiencing the disease.\u0000\u0000\u0000METHODS\u0000Using the James Lind Alliance approach to research priority setting, a 10-member steering committee comprised of current and former pediatric IBD patients, caregivers, and clinicians was formed. A national survey, disseminated across Canada, elicited uncertainties which were divided into unanswered and answered research questions. Subsequently a research prioritization survey was disseminated where respondents ranked their top 20 research uncertainties. A final prioritization meeting was held to agree upon the top 10 uncertainties.\u0000\u0000\u0000RESULTS\u0000From 1209 research questions submitted by 363 participants, the list was reduced to 105 indicative questions that were within scope and deemed unanswered in the literature. Via the national research prioritization survey, this list was further reduced. The top 10 uncertainties identified at the final research consensus meeting, with 21 participants from all stakeholder groups, included: \"What are the causes of IBD?\", \"Can IBD be prevented?\", \"What role does diet have in the management of pediatric IBD?\". Other questions concerned flare ups, biomarkers, optimal patient education, long-term effects of medication and early-diagnosis, role of psychological support, and optimal approach to diagnosis.\u0000\u0000\u0000CONCLUSION\u0000This research adds a unique perspective by deriving a list of pediatric IBD research uncertainties important by patients and caregivers, as well as clinicians.","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79343116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-05-15DOI: 10.1097/MPG.0000000000002371
Ruben J. Colman, J. W. Woo Baidal, J. Zitsman, Ali A. Mencin
OBJECTIVES Esophagogastroduodenoscopy (EGD) is often performed to evaluate for mucosal and anatomical abnormalities prior to vertical sleeve gastrectomy (SG). However, little is known about how pre-bariatric EGD in adolescents influences clinical management or outcome. Our aim was to assess if an abnormal pre-bariatric EGD resulted in interventions or modification of bariatric surgery. METHODS We performed a retrospective cohort study of adolescents undergoing evaluation for bariatric surgery. We obtained demographic and anthropometric data in addition to EGD findings, biopsy pathology, gastrointestinal symptoms and surgical outcomes. An EGD was considered abnormal if either abnormal gross findings or abnormal pathology was reported. Patients were followed until a 6-week post-op visit. RESULTS Of 134 patients presenting for evaluation, 94 (70%) underwent pre-operative EGD. Fifty-one (54%) had a normal EGD and 43 (46%) had EGD abnormalities including 7 with an anatomical abnormality and 36 with mild mucosal abnormalities. Among patients with EGD abnormalities 22% received medical intervention including proton pump inhibitors (PPI) administration (n = 10) and H. pylori eradication (n = 11). GI symptoms were the only predictor of EGD abnormalities (odds ratio (OR) 4.9: 95% CI, 1.6-15.0; p < 0.001). No factors predicted likelihood of a post-EGD intervention. An abnormal EGD did not correlate with any post-operative complications. CONCLUSIONS In this cohort of adolescents undergoing evaluation for SG, 46% had an abnormal EGD, of which 22% received a medical intervention. Symptoms were the only predictor of EGD abnormalities. Abnormal EGD findings were not associated with modification of the surgery or any adverse outcome.
{"title":"Upper GI Endoscopy in Adolescents with Severe Obesity Prior to Vertical Sleeve Gastrectomy.","authors":"Ruben J. Colman, J. W. Woo Baidal, J. Zitsman, Ali A. Mencin","doi":"10.1097/MPG.0000000000002371","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002371","url":null,"abstract":"OBJECTIVES\u0000Esophagogastroduodenoscopy (EGD) is often performed to evaluate for mucosal and anatomical abnormalities prior to vertical sleeve gastrectomy (SG). However, little is known about how pre-bariatric EGD in adolescents influences clinical management or outcome. Our aim was to assess if an abnormal pre-bariatric EGD resulted in interventions or modification of bariatric surgery.\u0000\u0000\u0000METHODS\u0000We performed a retrospective cohort study of adolescents undergoing evaluation for bariatric surgery. We obtained demographic and anthropometric data in addition to EGD findings, biopsy pathology, gastrointestinal symptoms and surgical outcomes. An EGD was considered abnormal if either abnormal gross findings or abnormal pathology was reported. Patients were followed until a 6-week post-op visit.\u0000\u0000\u0000RESULTS\u0000Of 134 patients presenting for evaluation, 94 (70%) underwent pre-operative EGD. Fifty-one (54%) had a normal EGD and 43 (46%) had EGD abnormalities including 7 with an anatomical abnormality and 36 with mild mucosal abnormalities. Among patients with EGD abnormalities 22% received medical intervention including proton pump inhibitors (PPI) administration (n = 10) and H. pylori eradication (n = 11). GI symptoms were the only predictor of EGD abnormalities (odds ratio (OR) 4.9: 95% CI, 1.6-15.0; p < 0.001). No factors predicted likelihood of a post-EGD intervention. An abnormal EGD did not correlate with any post-operative complications.\u0000\u0000\u0000CONCLUSIONS\u0000In this cohort of adolescents undergoing evaluation for SG, 46% had an abnormal EGD, of which 22% received a medical intervention. Symptoms were the only predictor of EGD abnormalities. Abnormal EGD findings were not associated with modification of the surgery or any adverse outcome.","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"104 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77324979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-03-01DOI: 10.1097/mpg.0000000000002291
{"title":"International Meeting Chronic Gastrointestinal Diseases From the Child to the Adult, April 4-6, 2019","authors":"","doi":"10.1097/mpg.0000000000002291","DOIUrl":"https://doi.org/10.1097/mpg.0000000000002291","url":null,"abstract":"","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74488617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-05DOI: 10.1097/MPG.0000000000002306
A. Agawu, Sarah E. Sheppard, Henry C. Lin
JPGN Volume 69, N CASE A 14-month-old boy with a history of moderate sensorineural hearing loss, language delay, and gross motor delay presents with several months of severe pruritus. His family tried over the counter ointments, oral diphenhydramine, and topical hydrocortisone without relief. He lost 1 pound over the preceding month (weight percentile less than the first percentile). He had no complaints of vomiting, abdominal pain, diarrhea, constipation, fatigue, or fever and no history of fractures, bleeding, jaundice, or xanthomas. Family history was unremarkable without liver disease, hearing loss, bleeding disorders, or consanguinity, and the family is of Hispanic ancestry. He had no known allergies or surgical history. Physical examination was notable for a weight of 7.7 kg (less than first percentile), head circumference 44.5 cm (second percentile), length 68.9 cm (less than first percentile). There was no jaundice, scaly skin, hepatosplenomegaly, hypotonia, or severe flexion contractures. To evaluate his symptoms, his primary care physician sent laboratory studies that showed: alanine aminotransferase (ALT)— 170 (normal: 0–29 IU/L); aspartate aminotransferase (AST)—152 (normal: 0–75 IU/L); alkaline phosphatase—879 (normal: 130 – 317 IU/L); total bilirubin—0.7 (normal: 0–1.2 mg/dL); gammaglutamyl transferase (GGT)—12 (normal: 0–65 IU/L). Further work-up focused on cholestatic processes that would require intervention and included a right upper quadrant ultrasound, alpha-1antitrypsin phenotype, and thyroid testing, all of which were normal. Total serum bile acids showed: ursodeoxycholic acid— 0.30 (normal: <1.9 mmol/L); cholic acids—26 (normal: <2.2 mmol/L); chenodeoxycholic acid—11 (normal: <5.8 mmol/ L); deoxycholic acid—<0.1 (normal: <3.3 mmol/L); total bile acids—37 (normal: <9.2 mmol/L). A cholestasis genetic panel was sent because of the abnormal bile acid testing. This identified a maternally inherited novel pathogenic nonsense mutation c.1246C>T (p.R416X) and a paternally inherited previously reported splice site mutation c.1225þ 5G>C in VPS33B, consistent with a diagnosis of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. Variants of uncertain significance were also identified in ATP8B1, LIPA, and CFTR. A single likely pathogenic mutation was also identified in the CFTR gene (c.[220C>T; 3808G>A]).
{"title":"A Novel VPS33B Mutation Causing a Mild Phenotype of ARC Syndrome.","authors":"A. Agawu, Sarah E. Sheppard, Henry C. Lin","doi":"10.1097/MPG.0000000000002306","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002306","url":null,"abstract":"JPGN Volume 69, N CASE A 14-month-old boy with a history of moderate sensorineural hearing loss, language delay, and gross motor delay presents with several months of severe pruritus. His family tried over the counter ointments, oral diphenhydramine, and topical hydrocortisone without relief. He lost 1 pound over the preceding month (weight percentile less than the first percentile). He had no complaints of vomiting, abdominal pain, diarrhea, constipation, fatigue, or fever and no history of fractures, bleeding, jaundice, or xanthomas. Family history was unremarkable without liver disease, hearing loss, bleeding disorders, or consanguinity, and the family is of Hispanic ancestry. He had no known allergies or surgical history. Physical examination was notable for a weight of 7.7 kg (less than first percentile), head circumference 44.5 cm (second percentile), length 68.9 cm (less than first percentile). There was no jaundice, scaly skin, hepatosplenomegaly, hypotonia, or severe flexion contractures. To evaluate his symptoms, his primary care physician sent laboratory studies that showed: alanine aminotransferase (ALT)— 170 (normal: 0–29 IU/L); aspartate aminotransferase (AST)—152 (normal: 0–75 IU/L); alkaline phosphatase—879 (normal: 130 – 317 IU/L); total bilirubin—0.7 (normal: 0–1.2 mg/dL); gammaglutamyl transferase (GGT)—12 (normal: 0–65 IU/L). Further work-up focused on cholestatic processes that would require intervention and included a right upper quadrant ultrasound, alpha-1antitrypsin phenotype, and thyroid testing, all of which were normal. Total serum bile acids showed: ursodeoxycholic acid— 0.30 (normal: <1.9 mmol/L); cholic acids—26 (normal: <2.2 mmol/L); chenodeoxycholic acid—11 (normal: <5.8 mmol/ L); deoxycholic acid—<0.1 (normal: <3.3 mmol/L); total bile acids—37 (normal: <9.2 mmol/L). A cholestasis genetic panel was sent because of the abnormal bile acid testing. This identified a maternally inherited novel pathogenic nonsense mutation c.1246C>T (p.R416X) and a paternally inherited previously reported splice site mutation c.1225þ 5G>C in VPS33B, consistent with a diagnosis of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. Variants of uncertain significance were also identified in ATP8B1, LIPA, and CFTR. A single likely pathogenic mutation was also identified in the CFTR gene (c.[220C>T; 3808G>A]).","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78284162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-01-01DOI: 10.1097/MPG.0000000000002539
Walter E. B. Sipe
{"title":"Commentary on \"Depression Screening in Pediatric IBD Clinics: Recommendations and a Toolkit for Implementation\".","authors":"Walter E. B. Sipe","doi":"10.1097/MPG.0000000000002539","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002539","url":null,"abstract":"","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87219386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-01-01DOI: 10.1097/MPG.0000000000002505
C. Jaramillo, S. Guthery, A. Lowichik, G. Stoddard, Taegun Kim, Yang Li, M. K. Jensen
BACKGROUND/RATIONALE Biliary atresia (BA) is a cholangiopathy characterized by bile flow obstruction due to destruction of the biliary tree. Without surgical correction with Kasai portoenterostomy (KPE), BA leads to death or liver transplant (LTx). Early-onset, progressive liver fibrosis is a defining characteristic of BA. Collagen hybridizing peptide (CHP) is a synthetic peptide which binds to denatured collagen strands allowing quantification of fibrosis. This technique has not been used on human liver tissue. The aim of this pilot study was to evaluate the utility of CHP as a measurement of quantitative fibrosis to allow earlier survival with native liver (SNL) prognostication. RESULTS We identified 21 patients with wedge liver biopsies available, of which 14 required LTx. No deaths occurred. Patients requiring LTx tended to be female with a significantly different mean bilirubin (p = 0.002), albumin (p = 0.001) and ALT (p = 0.03) at 3-months post-KPE. By 1-year post-KPE, 50% of patients in the high-CHP intensity group required LTx versus 27% in the low-CHP. Overall, fibrosis as quantified by CHP at time of KPE was associated with more than three-times the risk of requiring LTx by 4-years of age (HR 3.6, 95%CI 1.15-10.93, p = 0.03). When controlling for gender and TB > 2 mg/dL and albumin at 3-months post-KPE, it predicted nearly seven times the risk of LTx (HR 6.89, 95%CI 1.38-34.32, p = 0.02). CONCLUSION Our results suggest that quantitative assessment of fibrosis at the time of KPE holds promise as an earlier predictor of LTx requirement in BA. A larger study is justified to assess quantitative fibrosis as a BA prognostic tool.
{"title":"Quantitative Liver Fibrosis Using Collagen Hybridizing Peptide to Predict Native Liver Survival in Biliary Atresia: A Pilot Study.","authors":"C. Jaramillo, S. Guthery, A. Lowichik, G. Stoddard, Taegun Kim, Yang Li, M. K. Jensen","doi":"10.1097/MPG.0000000000002505","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002505","url":null,"abstract":"BACKGROUND/RATIONALE Biliary atresia (BA) is a cholangiopathy characterized by bile flow obstruction due to destruction of the biliary tree. Without surgical correction with Kasai portoenterostomy (KPE), BA leads to death or liver transplant (LTx). Early-onset, progressive liver fibrosis is a defining characteristic of BA. Collagen hybridizing peptide (CHP) is a synthetic peptide which binds to denatured collagen strands allowing quantification of fibrosis. This technique has not been used on human liver tissue. The aim of this pilot study was to evaluate the utility of CHP as a measurement of quantitative fibrosis to allow earlier survival with native liver (SNL) prognostication. RESULTS We identified 21 patients with wedge liver biopsies available, of which 14 required LTx. No deaths occurred. Patients requiring LTx tended to be female with a significantly different mean bilirubin (p = 0.002), albumin (p = 0.001) and ALT (p = 0.03) at 3-months post-KPE. By 1-year post-KPE, 50% of patients in the high-CHP intensity group required LTx versus 27% in the low-CHP. Overall, fibrosis as quantified by CHP at time of KPE was associated with more than three-times the risk of requiring LTx by 4-years of age (HR 3.6, 95%CI 1.15-10.93, p = 0.03). When controlling for gender and TB > 2 mg/dL and albumin at 3-months post-KPE, it predicted nearly seven times the risk of LTx (HR 6.89, 95%CI 1.38-34.32, p = 0.02). CONCLUSION Our results suggest that quantitative assessment of fibrosis at the time of KPE holds promise as an earlier predictor of LTx requirement in BA. A larger study is justified to assess quantitative fibrosis as a BA prognostic tool.","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78418398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-01-01DOI: 10.1097/MPG.0000000000002535
Nidhi P. Goyal, M. C. Sawh, Patricia A. Ugalde-Nicalo, J. Angeles, J. Proudfoot, K. Newton, M. Middleton, C. Sirlin, J. Schwimmer
OBJECTIVES Early-phase pediatric nonalcoholic fatty liver disease (NAFLD) clinical trials are designed with non-invasive parameters to assess potential efficacy. Increasingly, these parameters include MRI-derived proton density fat fraction (PDFF) and MR elastography (MRE)-derived shear stiffness as biomarkers of hepatic steatosis and fibrosis, respectively. Understanding fluctuations in these measures is essential for calculating trial sample sizes, interpreting results, and planning clinical drug trials in children with NAFLD. Lack of such data in children comprises a critical knowledge gap. Therefore, the primary aim of this study was to assess whole-liver MRI-PDFF change in adolescents with nonalcoholic steatohepatitis (NASH) over 12 weeks. METHODS Adolescents 12-19 years with biopsy-proven NASH undergoing standard-of-care treatment were enrolled. Baseline and week-12 assessments of anthropometrics, transaminases, MRI-PDFF, and MRE-stiffness were obtained. RESULTS Fifteen adolescents were included (mean age 15.7 [SD 2.9] years). Hepatic MRI-PDFF was stable over 12 weeks (mean absolute change -0.8%, p = 0.24). Correlation between baseline and week-12 values of MRI-PDFF was high (ICC = 0.97, 95% CI 0.90 - 0.99). MRE-stiffness was stable (mean percentage change 2.7%, p = 0.44); correlation between baseline and week-12 values was moderate (ICC = 0.47; 95% CI: 0, 0.79). Changes in weight, BMI, and aminotransferases were not statistically significant. CONCLUSIONS In adolescents with NASH, fluctuations in hepatic MRI-PDFF and MRE-stiffness over 12 weeks of standard-of-care were small. These data on the natural fluctuations in quantitative imaging biomarkers can serve as a reference for interventional trials in pediatric NASH and inform the interpretation and planning of clinical trials.
{"title":"Evaluation of Quantitative Imaging Biomarkers for Early Phase Clinical Trials of Steatohepatitis in Adolescents.","authors":"Nidhi P. Goyal, M. C. Sawh, Patricia A. Ugalde-Nicalo, J. Angeles, J. Proudfoot, K. Newton, M. Middleton, C. Sirlin, J. Schwimmer","doi":"10.1097/MPG.0000000000002535","DOIUrl":"https://doi.org/10.1097/MPG.0000000000002535","url":null,"abstract":"OBJECTIVES Early-phase pediatric nonalcoholic fatty liver disease (NAFLD) clinical trials are designed with non-invasive parameters to assess potential efficacy. Increasingly, these parameters include MRI-derived proton density fat fraction (PDFF) and MR elastography (MRE)-derived shear stiffness as biomarkers of hepatic steatosis and fibrosis, respectively. Understanding fluctuations in these measures is essential for calculating trial sample sizes, interpreting results, and planning clinical drug trials in children with NAFLD. Lack of such data in children comprises a critical knowledge gap. Therefore, the primary aim of this study was to assess whole-liver MRI-PDFF change in adolescents with nonalcoholic steatohepatitis (NASH) over 12 weeks. METHODS Adolescents 12-19 years with biopsy-proven NASH undergoing standard-of-care treatment were enrolled. Baseline and week-12 assessments of anthropometrics, transaminases, MRI-PDFF, and MRE-stiffness were obtained. RESULTS Fifteen adolescents were included (mean age 15.7 [SD 2.9] years). Hepatic MRI-PDFF was stable over 12 weeks (mean absolute change -0.8%, p = 0.24). Correlation between baseline and week-12 values of MRI-PDFF was high (ICC = 0.97, 95% CI 0.90 - 0.99). MRE-stiffness was stable (mean percentage change 2.7%, p = 0.44); correlation between baseline and week-12 values was moderate (ICC = 0.47; 95% CI: 0, 0.79). Changes in weight, BMI, and aminotransferases were not statistically significant. CONCLUSIONS In adolescents with NASH, fluctuations in hepatic MRI-PDFF and MRE-stiffness over 12 weeks of standard-of-care were small. These data on the natural fluctuations in quantitative imaging biomarkers can serve as a reference for interventional trials in pediatric NASH and inform the interpretation and planning of clinical trials.","PeriodicalId":16725,"journal":{"name":"Journal of Pediatric Gastroenterology & Nutrition","volume":"305 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78255448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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