Prospective study of quantitative liver MRI in cystic fibrosis: feasibility and comparison to PUSH cohort ultrasound.

BACKGROUND: Pediatric radiologists can identify a liver ultrasound (US) pattern predictive of progression to advanced liver disease. However, reliably discriminating these US patterns remains difficult. Quantitative magnetic resonance imaging (MRI) may provide an objective measure of liver disease in cystic fibrosis (CF). OBJECTIVE: The purpose of this study was to determine if quantitative MRI, including MR elastography, is feasible in children with CF and to determine how quantitative MRI-derived metrics compared to a research US. MATERIALS AND METHODS: A prospective, multi-institutional trial was performed evaluating CF participants who underwent a standardized MRI. At central review, liver stiffness, fat fraction, liver volume, and spleen volume were obtained. Participants whose MRI was performed within 1 year of US were classified by US pattern as normal, homogeneous hyperechoic, heterogeneous, or nodular. Each MRI measure was compared among US grade groups using the Kruskal-Wallis test. RESULTS: Ninety-three participants (51 females [54.8%]; mean 15.6 years [range 8.1-21.7 years]) underwent MRI. MR elastography was feasible in 87 participants (93.5%). Fifty-eight participants had an US within 1 year of MRI. In these participants, a nodular liver had significantly higher stiffness (P<0.01) than normal or homogeneous hyperechoic livers. Participants with a homogeneous hyperechoic liver had a higher fat fraction (P<0.005) than others. CONCLUSION: MR elastography is feasible in children with CF. Participants with a nodular pattern had higher liver stiffness supporting the US determination of advanced liver disease. Participants with a homogeneous hyperechoic pattern had higher fat fractions supporting the diagnosis of steatosis.

Health-related Quality of Life in a Prospective Study of Ultrasound to Detect Cystic Fibrosis-related Liver Disease in Children.

OBJECTIVES: Cystic fibrosis liver disease (CFLD) begins early in life. Symptoms may be vague, mild, or nonexistent. Progressive liver injury may be associated with decrements in patient health before liver disease is clinically apparent. We examined Health-Related Quality of Life (HRQOL) in children enrolled in a multi-center study of CFLD to determine the impact of early CFLD on general and disease-specific QOL. METHODS: Ultrasound (US) patterns of normal (NL), heterogeneous (HTG), homogeneous (HMG), or nodular (NOD) were assigned in a prospective manner to predict those at risk for advanced CFLD. Parents were informed of results. We assessed parent/child-reported (age ≥5 years) HRQOL by PedsQL 4.0 Generic Core and CF Questionnaire-revised (CFQ-R) prior to US and annually. HRQOL scores were compared by US pattern at baseline (prior to US), between baseline and 1 year and at 5 years. Multivariate analysis of variance (MANOVA) with Hotelling-Lawley trace tested for differences among US groups. RESULTS: Prior to US, among 515 participants and their parents there was no evidence that HTG or NOD US was associated with reduced PedsQL/CFQ-R at baseline. Parents of NOD reported no change in PedsQL/CFQ-R over the next year. Child-report PedsQL/CFQ-R (95 NL, 20 NOD) showed improvement between baseline and year 5 for many scales, including Physical Function. Parents of HMG children reported improved CFQ-R scores related to weight. CONCLUSIONS: Early undiagnosed or pre-symptomatic liver disease had no impact on generic or disease-specific HRQoL, and HRQoL was remarkably stable in children with CF regardless of liver involvement.

Creation of a Pediatric Choledocholithiasis Prediction Model.

BACKGROUND: Definitive non-invasive detection of pediatric choledocholithiasis could allow more efficient identification of those patients who are most likely to benefit from therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for stone extraction. OBJECTIVE: To craft a pediatric choledocholithiasis prediction model using a combination of commonly available serum laboratory values and ultrasound results. METHODS: A retrospective review of laboratory and imaging results from 316 pediatric patients who underwent intraoperative cholangiogram or ERCP due to suspicion of choledocholithiasis were collected and compared to presence of common bile duct stones on cholangiography. Multivariate logistic regression with supervised machine learning was used to create a predictive scoring model. Monte-Carlo cross-validation was used to validate the scoring model and a score threshold that would provide at least 90% specificity for choledocholithiasis was determined in an effort to minimize non-therapeutic ERCP. RESULTS: Alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, and common bile duct diameter via ultrasound were found to be the key clinical variables to determine the likelihood of choledocholithiasis. The dictated specificity threshold of 90.3% yielded a sensitivity of 40.8% and overall accuracy of 71.5% in detecting choledocholithiasis. Positive predictive value was 71.4% and negative predictive value was 72.1%. CONCLUSION: Our novel pediatric choledocholithiasis predictive model is a highly specific tool to suggest ERCP in the setting of likely choledocholithiasis.

Gastrointestinal Factors Associated With Hospitalization in Infants With Cystic Fibrosis: Results From the Baby Observational and Nutrition Study.

OBJECTIVES: To identify factors that increase the risk of gastrointestinal-related (GI-related) hospitalization of infants with cystic fibrosis (CF) during the first year of life. METHODS: The Baby Observational and Nutrition Study was a longitudinal, observational cohort of 231 infants diagnosed with CF by newborn screening. We performed a post-hoc assessment of the frequency and indications for GI-related admissions during the first year of life. RESULTS: Sixty-five participants had at least one admission in the first 12 months of life. High pancreatic enzyme replacement therapy (PERT) dosing (>2000 lipase units/kg per meal; hazard ratio [HR] = 14.75, P = 0.0005) and use of acid suppressive medications (HR = 4.94, P = 0.01) during the study period were positively associated with subsequent GI-related admissions. High levels of fecal calprotectin (fCP) (>200 µg/g) and higher relative abundance of fecal Klebsiella pneumoniae were also positively associated with subsequent GI-related admissions (HR = 2.64, P = 0.033 and HR = 4.49, P = 0.002, respectively). During the first 12 months of life, participants with any admission had lower weight-for-length z scores (WLZ) (P = 0.01). The impact of admission on WLZ was particularly evident in participants with a GI-related admission (P < 0.0001). CONCLUSIONS: Factors associated with a higher risk for GI-related admission during the first 12 months include high PERT dosing, exposure to acid suppressive medications, higher fCP levels, and/or relative abundance of fecal K pneumoniae early in life. Infants with CF requiring GI-related hospitalization had lower WLZ at 12 months of age than those not admitted as well as those admitted for non-GI-related indications.

North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the Society for Pediatric Radiology Joint Position Paper on Noninvasive Imaging of Pediatric Pancreatitis: Literature Summary and Recommendations.

ABSTRACT: The reported incidence of pediatric pancreatitis is increasing. Noninvasive imaging, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), play important roles in the diagnosis, staging, follow-up, and management of pancreatitis in children. In this position paper, generated by members of the Pancreas Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the Abdominal Imaging Committee of The Society for Pediatric Radiology (SPR), we review the roles of noninvasive imaging in pediatric acute, acute recurrent, and chronic pancreatitis. We discuss available evidence related to noninvasive imaging, highlighting evidence specific to pediatric populations, and we make joint recommendations for use of noninvasive imaging. Further, we highlight the need for research to define the performance and role of noninvasive imaging in pediatric pancreatitis.

Medical Management of Chronic Pancreatitis in Children: A Position Paper by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee.

ABSTRACT: This position paper summarizes the current understanding of the medical management of chronic pancreatitis (CP) in children in light of the existing medical literature, incorporating recent advances in understanding of nutrition, pain, lifestyle considerations, and sequelae of CP. This article complements and is intended to integrate with parallel position papers on endoscopic and surgical aspects of CP in children. Concepts and controversies related to pancreatic enzyme replacement therapy (PERT), the use of antioxidants and other CP medical therapies are also reviewed. Highlights include inclusion of tools for medical decision-making for PERT, CP-related diabetes, and multimodal pain management (including an analgesia ladder). Gaps in our understanding of CP in children and avenues for further investigations are also reviewed.

Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.

OBJECTIVE: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease. STUDY DESIGN: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease. RESULTS: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern). CONCLUSIONS: Research liver ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.

COVID-19-associated Multisystem Inflammatory Syndrome in Children Presenting as Acute Pancreatitis.

In April 2020, a newly recognized pediatric disorder associated with COVID-19 characterized by significant inflammation with symptoms resembling Kawasaki disease was described by medical teams in the United States, the United Kingdom, and Italy. Before these reports, data from the initial COVID-19 outbreaks in China had not found the virus to cause significant morbidity or mortality in children. To date, pancreatitis has not yet been reported in either acute SARS-CoV-2 infection in children or the subsequent inflammatory syndrome. We describe a patient who presented with acute pancreatitis before rapidly progressing to multisystem organ dysfunction consistent with multisystem inflammatory syndrome in children due to COVID-19. Clinicians should be aware that in the context of the COVID-19 pandemic, pancreatitis can be an early presentation of multisystem inflammatory syndrome in children.

A Multidisciplinary Approach to Pretransplant and Posttransplant Management of Cystic Fibrosis-Associated Liver Disease.

Approximately 5%-10% of patients with cystic fibrosis (CF) will develop advanced liver disease with portal hypertension, representing the third leading cause of death among patients with CF. Cystic fibrosis with advanced liver disease and portal hypertension (CFLD) represents the most significant risk to patient mortality, second only to pulmonary or lung transplant complications in patients with CF. Currently, there is no medical therapy to treat or reverse CFLD. Liver transplantation (LT) in patients with CFLD with portal hypertension confers a significant survival advantage over those who do not receive LT, although the timing in which to optimize this benefit is unclear. Despite the value and efficacy of LT in selected patients with CFLD, established clinical criteria outlining indications and timing for LT as well as disease-specific transplant considerations are notably absent. The goal of this comprehensive and multidisciplinary report is to present recommendations on the unique CF-specific pre- and post-LT management issues clinicians should consider and will face.

Liver Ultrasound Patterns in Children With Cystic Fibrosis Correlate With Noninvasive Tests of Liver Disease.

OBJECTIVES: Early identification of children with cystic fibrosis (CF) at risk for severe liver disease (CFLD) would enable targeted study of preventative therapies. There is no gold standard test for CFLD. Ultrasonography (US) is used to identify CFLD, but with concerns for its diagnostic accuracy. We aim to determine if differences in standard blood tests, imaging variables and noninvasive liver fibrosis indices correlate with liver US patterns, and thus provide supportive evidence that a heterogeneous US liver pattern reflects clinically relevant liver disease. METHODS: We studied baseline research abdominal US and bloodwork from 244 children with pancreatic insufficient CF, ages 3 to 12 years, enrolled in a prospective study of the ability of US to predict CF cirrhosis (PUSH study). Children with a heterogeneous (HTG) liver pattern on US (n = 62) were matched 1 : 2 in design with children with normal US (NL, n = 122). Analyses included children with nodular (NOD, n = 22) and homogeneous hyperechoic (HMG, n = 38) livers. RESULTS: Univariate analysis showed significant differences between US groups for standard blood tests, spleen size, and noninvasive liver fibrosis indices. Multivariable models discriminated NOD versus NL with excellent accuracy (AUROC 0.96). Models also distinguish HTG versus NL (AUROC 0.76), NOD versus HTG (0.78), and HMG versus NL (0.79). CONCLUSIONS: Liver US patterns in children with CF correlate with platelet count, spleen size and indices of liver fibrosis. Multivariable models of these biomarkers have excellent discriminating ability for NL versus NOD, and good ability to distinguish other US patterns, suggesting that US patterns correlate with clinically relevant liver disease.

Early detection of hepatobiliary involvement in cystic fibrosis: Biomarkers, radiologic methods, and genetic influences.

Cystic fibrosis-related hepatobiliary involvement (CFHBI) is a term used to describe a spectrum of hepatobiliary involvement ranging from a transient elevation of transaminase levels to advanced cystic fibrosis-associated liver disease (aCFLD). While CFHBI is common among people with cystic fibrosis (PwCF), aCFLD is rare impacting only approximately 5%-10% of the CF population. After respiratory/cardiorespiratory issues and transplant-related complications, aCFLD is now the 4th leading cause of mortality among PwCF. Additionally, aCFLD is an independent predictor of all-cause mortality and is associated with significant morbidity. Despite this recognition, our ability to predict those patients at greatest risk for aCFLD, identify early aCFLD, and monitor the incremental progression of CFHBI is lacking. Here, we review the strengths and weaknesses of the common biomarkers and imaging modalities used in the evaluation and monitoring of CFHBI, as well as the current understanding of genetic modifiers related to aCFLD.

Estimating minimal clinically important difference (MCID) for gastrointestinal symptoms in cystic fibrosis.

BACKGROUND: Minimal clinically important difference (MCID) is important to establish as a meaningful outcome in research when using patient reported outcome measures (PROMs). We determined the MCID using the distribution-based approach for three measurements used as part of the GALAXY study, which is an observational prospective study on gastrointestinal (GI) symptoms in cystic fibrosis (CF). METHODS: Four hundred and two persons with cystic fibrosis (PwCF) participated in the GALAXY study, all with baseline values available for all questionnaires. Mean age was 20.9 years (2.1- 61.1) with 75 females and 94 males under the age of 18 (42.04 %) and 118 females and 115 males aged 18 or older (57.99 %). MCID was measured for Patient Assessment of Constipation Symptoms (PAC-SYM), Patient Assessment of Upper Gastrointestinal Symptoms (PAGI-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL) and their subscales. Two distribution-based approaches, defined as multiplications of the standard deviation (SD) or standard error of the mean (SEM), were used to approximate the MCID. RESULTS: The two distribution-based approaches for determining the MCID estimates produced comparable results in trends in MCIDs across the subscales and total scores. In general, MCID estimates of subscales for all three measurements were higher than their total score MCIDs. The one-half SD- and SEM-based MCID estimates for total scores of each questionnaire are as follows: PAC-SYM: 0.26 and 0.14; PAGI-SYM: 0.32 and 0.15; PAC-QOL: 0.27 and 0.18, respectively. CONCLUSION: This paper establishes initial MCIDs estimated by the distribution-based approach for the PAC-SYM, PAGI-SYM and PAC-QOL that can now be used to evaluate interventional studies that may impact gastrointestinal symptoms in PwCF.

Interventions for Pancreatitis-New Approaches, Knowledge Gaps, and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

ABSTRACT: There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.

Need to study simplification of gastrointestinal medication regimen in cystic fibrosis in the era of highly effective modulators.

INTRODUCTION: The success of highly effective modulator therapy (HEMT) has led to consideration of simpler regimens for people with CF (PwCF) with opportunities to modify burdensome regimens. Despite the intuitive appeal of discontinuing chronic therapies no longer necessary, this process should be pursued systematically to ensure safety, adherence, and validate patient-centered preferences. We designed a questionnaire to determine the state of use of acid-suppressive medications (ASM) and pancreatic enzyme therapy (PERT), current self-withdrawal and provider-directed withdrawal practices, and interest in a standardized withdrawal study. METHODS: In collaboration with CF Foundation (CFF), a questionnaire was developed and distributed to members of Community Voice (CV, comprised of PwCF and their loved ones), and CF providers regarding the need to study simplifying the gastrointestinal (GI) regimen for PwCF on HEMT. RESULTS: Approximately 20-40% of CV or CF providers have decreased or stopped ASM for those on HEMT. For PERT, CV and CF providers have decreased dose (34%-48% and approximately 25%, respectively) more often than having stopped it altogether (13%-24% and 3%-12%, respectively). Cumulatively, there is interest in pursuing research in this area (86% CV and 89% CF providers) and willingness to enroll in such a study (80% CV and 89% CF providers). CONCLUSION: Systematically studying the withdrawal of common GI medications, ASM and PERT, is important to CV and CF providers. Decreases in dosing and withdrawal are already taking place without evidence to support this practice. This questionnaire is the first step in designing a GI medication simplification study in PwCF on HEMT.

Multicenter prospective study showing a high gastrointestinal symptom burden in cystic fibrosis.

BACKGROUND AND AIMS: People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms affecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF). METHODS: Eligible participants ≥2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models. RESULTS: Of 402 enrolled, 58% were ≥ 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants ≥18 versus <18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatisfaction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47). CONCLUSION: GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interventions. CLINICALTRIALS: GOV: NCT03801993.

Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease.

BACKGROUND: This study examines whether heterogeneous (HTG) pattern on liver ultrasound (US) identifies children at risk for advanced cystic fibrosis liver disease (aCFLD). METHODS: Prospective 6-year multicenter case-controlled cohort study. Children with pancreatic insufficient cystic fibrosis (CF) aged 3-12 years without known cirrhosis underwent screening US. Participants with HTG were matched (by age, Pseudomonas infection status and center) 1:2 with participants with normal (NL) US pattern. Clinical status and laboratory data were obtained annually and US bi-annually for 6 years. Primary endpoint was development of nodular (NOD) US pattern consistent with aCFLD. RESULTS: 722 participants underwent screening US, with 65 HTG and 592 NL. Final cohort included 55 HTG and 116 NL with ≥ 1 follow-up US. ALT, AST, GGTP, FIB-4, GPR and APRI were higher, and platelets were lower in HTG compared to NL. HTG had a 9.5-fold increased incidence (95% confidence interval [CI]:3.4, 26.7, p<0.0001, 32.7% vs 3.4%) of NOD versus NL. HTG had a sensitivity of 82% and specificity of 75% for subsequent NOD. Negative predictive value of a NL US for subsequent NOD was 96%. Multivariate logistic prediction model that included baseline US, age, and log(GPR) improved the C-index to 0.90 compared to only baseline US (C-index 0.78). Based on survival analysis, 50% of HTG develop NOD after 8 years. CONCLUSIONS: Research US finding of HTG identifies children with CF with a 30-50% risk for aCFLD. A score based on US pattern, age and GPR may refine the identification of individuals at high risk for aCFLD. CLINICAL TRIAL REGISTRATION: Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF: NCT 01,144,507 (observational study, no consort checklist).

Long-term follow-up and liver outcomes in children with cystic fibrosis and nodular liver on ultrasound in a multi-center study.

BACKGROUND: Nodular liver (NOD) in cystic fibrosis (CF) suggests advanced CF liver disease (aCFLD); little is known about progression of liver disease (LD) after detection of sonographic NOD. METHODS: Clinical, laboratory, and ultrasound (US) data from Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in CFLD Study participants with NOD at screening or follow-up were compared with normal (NL). Linear mixed effects models were used for risk factors for LD progression and Kaplan-Meier estimator for time-to-event. RESULTS: 54 children with NOD (22 screening, 32 follow-up) and 112 NL were evaluated. Baseline (BL) and trajectory of forced expiratory volume, forced vital capacity, height/BMI z-scores were similar in NOD vs NL. Platelets were lower in NOD at BL (250 vs 331×103/microL; p < 0.001) and decreased by 8600/year vs 2500 in NL. Mean AST to Platelet Ratio Index (1.1 vs 0.4; p < 0.001), Fibrosis-4 Index (0.4 vs 0.2, p < 0.001), and spleen size z-score (SSZ) [1.5 vs 0.02; p < 0.001] were higher in NOD at BL; SSZ increased by 0.5 unit/year in NOD vs 0.1 unit/year in NL. Median liver stiffness (LSM) by transient elastography was higher in NOD (8.2 kPa, IQR 6-11.8) vs NL (5.3, 4.2-7, p < 0.0001). Over 6.3 years follow-up (1.3-10.3), 6 NOD had esophageal varices (cumulative incidence in 10 years: 20%; 95% CI: 0.0%, 40.0%), 2 had variceal bleeding, and 2 underwent liver transplantation; none had ascites or hepatic encephalopathy. No NL experienced liver-related events. CONCLUSIONS: NOD developed clinically evident portal hypertension faster than NL without worse growth or lung disease.