Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations.

Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. A committee of hepatologists, gastroenterologists, pulmonologists, pharmacists, nurses, dietitians, individuals with CF, and the parents of a child with CF devised "population, intervention, comparison, and outcome" questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each population, intervention, comparison, and outcome question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to the formulation of final recommendations. Thirty-one population, intervention, comparison, and outcome questions were assembled, 6401 manuscripts were title screened for relevance, with 1053 manuscripts undergoing detailed full-text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring, and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment.

Divergent roles of estrogen receptor subtypes in regulating estrogen-modulated colonic ion transports and epithelial repair.

Although it was described previously for estrogen (E2) regulation of intestinal epithelial Cl- and HCO3- secretion in sex difference, almost nothing is known about the roles of estrogen receptor (ER) subtypes in regulating E2-modulated epithelial ion transports and epithelial restitution. Here, we aimed to investigate ERα and ERß subtypes in the regulation of E2-modulated colonic epithelial HCO3- and Cl- secretion and epithelial restitution. Through physiological and biochemical studies, in combination of genetic knockdown, we showed that ERα attenuated female colonic Cl- secretion but promoted Ca2+-dependent HCO3- secretion via store-operated calcium entry (SOCE) mechanism in mice. However, ERß attenuated HCO3- secretion by inhibiting Ca2+via the SOCE and inhibiting cAMP via protein kinases. Moreover, ERα but not ERß promoted epithelial cell restitution via SOCE/Ca2+ signaling. ERα also enhanced cyclin D1, proliferating cell nuclear antigen, and ß-catenin expression in normal human colonic epithelial cells. All ERα-mediated biological effects could be attenuated by its selective antagonist and genetic knockdown. Finally, both ERα and ERß were expressed in human colonic epithelial cells and mouse colonic tissues. We therefore conclude that E2 modulates complex colonic epithelial HCO3- and Cl- secretion via ER subtype-dependent mechanisms and that ERα is specifically responsible for colonic epithelial regeneration. This study provides novel insights into the molecular mechanisms of how ERα and ERß subtypes orchestrate functional homeostasis of normal colonic epithelial cells.

Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption by blocking TRPV4 channels in healthy and colitic mice.

Although capsaicin has been studied extensively as an activator of the transient receptor potential vanilloid cation channel subtype 1 (TRPV1) channels in sensory neurons, little is known about its TRPV1-independent actions in gastrointestinal health and disease. Here, we aimed to investigate the pharmacological actions of capsaicin as a food additive and medication on intestinal ion transporters in mouse models of ulcerative colitis (UC). The short-circuit current (Isc) of the intestine from WT, TRPV1-, and TRPV4-KO mice were measured in Ussing chambers, and Ca2+ imaging was performed on small intestinal epithelial cells. We also performed Western blots, immunohistochemistry, and immunofluorescence on intestinal epithelial cells and on intestinal tissues following UC induction with dextran sodium sulfate. We found that capsaicin did not affect basal intestinal Isc but significantly inhibited carbachol- and caffeine-induced intestinal Isc in WT mice. Capsaicin similarly inhibited the intestinal Isc in TRPV1 KO mice, but this inhibition was absent in TRPV4 KO mice. We also determined that Ca2+ influx via TRPV4 was required for cholinergic signaling-mediated intestinal anion secretion, which was inhibited by capsaicin. Moreover, the glucose-induced jejunal Iscvia Na+/glucose cotransporter was suppressed by TRPV4 activation, which could be relieved by capsaicin. Capsaicin also stimulated ouabain- and amiloride-sensitive colonic Isc. Finally, we found that dietary capsaicin ameliorated the UC phenotype, suppressed hyperaction of TRPV4 channels, and rescued the reduced ouabain- and amiloride-sensitive Isc. We therefore conclude that capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption predominantly by blocking TRPV4 channels to exert its beneficial anti-colitic action.

Notch signaling inactivation by small molecule γ-secretase inhibitors restores the multiciliated cell population in the airway epithelium.

Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases.NEW & NOTEWORTHY Our findings show that low-dose, short-term topical or systemic γ-secretase inhibitor treatment may lead to restoration of multiciliated cells without toxicity and potentially improve epithelial function in a wide range of chronic lung diseases.

Bone health in children with recurrent and chronic pancreatitis: A multi-center cross sectional analysis.

BACKGROUND/OBJECTIVES: Bone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied. METHODS: This retrospective study was performed at three sites and included data from INSPPIRE-2. RESULTS: Of the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 ± 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score < -2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score < -2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p = 0.03, respectively). CONCLUSION: Children with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted.

Pediatric Drug-Associated Pancreatitis Reveals Concomitant Risk Factors and Poor Reliability of Causality Scoring: Report From INSPPIRE.

OBJECTIVES: Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. METHODS: Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode. RESULTS: Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores. CONCLUSIONS: Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP.

Targeted replacement of full-length CFTR in human airway stem cells by CRISPR-Cas9 for pan-mutation correction in the endogenous locus.

Cystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the CF transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR-Cas9 and two adeno-associated viruses (AAVs) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial epithelial cells (HBECs). The modified cells were enriched to obtain 60%-80% tCD19+ UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies.

CFTR genotype analysis of Asians in international registries highlights disparities in the diagnosis and treatment of Asian patients with cystic fibrosis.

PURPOSE: Cystic fibrosis (CF) is not well-characterized in Asians, potentially resulting in delayed diagnosis and poor prognosis. We characterized CF in Asian subgroups to address these disparities. METHODS: De-identified ethnicity and CFTR variant data were obtained from the United States, United Kingdom, and Canadian CF registries. We measured the prevalence of CF, CFTR variant allele frequencies, effectiveness of screening panels, and eligibility for modulator therapies. RESULTS: The prevalence of CF was 1 in 74,982 people (Canada) to 1 in 13,340 people (United Kingdom) for South Asians and 1 in 256,541 (Canada) to 1 in 52,563 (United Kingdom) for other Asians, suggesting 26,000 to 146,000 patients with CF in South Asia. p.(F508del) variant was markedly less frequent in Asians than in non-Hispanic Whites. Splicing and nonsense variants occurred at high allelic frequencies in Asians, resulting in 41% to 49% of South Asians and 21% to 39% of other Asians being ineligible for CFTR modulator therapies. Hologic/EU2v1 panels failed to identify 37% to 47% of South Asian and 23% to 46% of other Asian patients with CF. CONCLUSIONS: Among Asians, CF appears to be more common in South Asians. A significant CF population may exist in South Asia. CFTR variants in South and other Asians markedly differ from non-Hispanic Whites causing inequities in newborn screening, diagnosis, and treatment. New strategies are necessary to mitigate these health care disparities.

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

OBJECTIVES: Chronic pancreatitis (CP) is rare in childhood but impactful because of its high disease burden. There is limited literature regarding the management of CP in children, specifically about the various surgical approaches. Herein, we summarize the current pediatric and adult literature and provide recommendations for the surgical management of CP in children. METHODS: The literature review was performed to include the scope of the problem, indications for operation, conventional surgical options as well as total pancreatectomy with islet autotransplantation, and outcomes following operations for CP. RESULTS: Surgery is indicated for children with debilitating CP who have failed maximal medical and endoscopic interventions. Surgical management must be tailored to the patient's unique needs, considering the anatomy and morphology of their disease. A conventional surgical approach (eg, drainage operation, partial resection, combination drainage-resection) may be considered in the presence of significant and uniform pancreatic duct dilation or an inflammatory head mass. Total pancreatectomy with islet autotransplantation is the best surgical option in patients with small duct disease. The presence of genetic risk factors often portends a suboptimal outcome following a conventional operation. CONCLUSIONS: The morphology of disease and the presence of genetic risk factors must be considered while determining the optimal surgical approach for children with CP. Surgical outcomes for CP are variable and depend on the type of intervention. A multidisciplinary team approach is needed to assure that the best possible operation is selected for each patient, their recovery is optimized, and their immediate and long-term postoperative needs are well-met.

Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children With Acute Recurrent or Chronic Pancreatitis.

OBJECTIVES: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). METHODS: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. RESULTS: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. CONCLUSIONS: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.

Health-Related Quality of Life in Pediatric Acute Recurrent or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors.

OBJECTIVES: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001). CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children.

Endoscopic Pancreatic Function Testing (ePFT) in Children: A Position Paper From the NASPGHAN Pancreas Committee.

ABSTRACT: Endoscopic pancreatic function testing (ePFT) is one of the few ways to directly diagnose exocrine pancreatic insufficiency, and considerable confusion regarding indications, utility, and interpretation of the test remains. This position paper of the Pancreas Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition reviews the history and indications for ePFT in children. We compare various methods in current practice and determine their strengths and limitations, and based on data from children and adults we provide guidance on a protocol on how to perform ePFT in children. Lastly, we pose areas in need of further research relating to ePFT in children.

Clinical use of shear-wave elastography for detecting liver fibrosis in children and adolescents with cystic fibrosis.

BACKGROUND: Complications from liver cirrhosis are a leading cause of death in children with cystic fibrosis. Identifying children at risk for developing liver cirrhosis and halting its progression are critical to reducing liver-associated mortality. OBJECTIVE: Quantitative US imaging, such as shear-wave elastography (SWE), might improve the detection of liver fibrosis in children with cystic fibrosis (CF) over gray-scale US alone. We incorporated SWE in our pediatric CF liver disease screening program and evaluated its performance using magnetic resonance (MR) elastography. MATERIALS AND METHODS: Ninety-four children and adolescents with CF underwent 178 SWE exams, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and platelet measurements. Of these, 27 children underwent 34 MR elastography exams. We evaluated SWE performance using 6-MHz and 9-MHZ point SWE, and 9-MHz two-dimensional (2-D) SWE. RESULTS: The 6-MHz point SWE was the only method that correlated with MR elastography (r=0.52; 95% confidence interval [CI] 0.20-0.74; P=0.003). SWE of 1.45 m/s distinguished normal from abnormal MR elastography (79% sensitivity, 100% specificity, 100% positive predictive value [PPV], 55% negative predictive value [NPV], area under the receiver operating characteristic [AUROC] curve 0.94). SWE of 1.84 m/s separated mild-moderate (3.00-4.77 kPa) from severe (>4.77 kPa) MR elastography (88% sensitivity, 86% specificity, 78% PPV, 93% NPV, AUROC 0.79). Elevations of AST, ALT, GGT and thrombocytopenia were associated with higher SWE. AST-to-platelet ratio index of 0.42, fibrosis-4 of 0.29, and GGT-to-platelet ratio of 1.43 all had >95% NPV for SWE >1.84 m/s. CONCLUSION: Given its correlation with MR elastography, SWE might be a clinically useful predictor of liver fibrosis. We identified imaging criteria delineating the use of SWE to identify increased liver stiffness in children with CF. With multicenter validation, these data might be used to improve the detection and monitoring of liver fibrosis in children with CF.

Pancreatic complications in children with cystic fibrosis.

PURPOSE OF REVIEW: The pancreas is highly affected in cystic fibrosis, with complications occurring early in childhood. This review highlights recent research in exocrine pancreatic function in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and discusses how these are affecting pancreatitis and exocrine pancreatic insufficiency (EPI) in children. Additionally, new research into exocrine--endocrine interactions sheds light on how CFTR dysfunction in ductal cells may affect beta cells. RECENT FINDINGS: Ivacaftor has disproved the hypothesis that EPI in children with cystic fibrosis is irreversible. Improvements in pancreatic function have increased pancreatitis episodes in some children and reduced them in others. Imaging advances are providing complementary methods for exocrine pancreatic function testing. New research into the interplay between the exocrine and endocrine components of the pancreas are elucidating the intertwined and complex relationship between the exocrine and endocrine pancreas. SUMMARY: Pancreatic complications contribute to the morbidity and mortality of children with cystic fibrosis. Increasing use of highly effective CFTR modulators will not only abrogate these but will also advance our understanding of pancreatic pathophysiology in cystic fibrosis. New frontiers into pancreatic gene therapy and exocrine--endocrine research will help provide new therapeutic opportunities for pancreatitis, EPI, and diabetes in cystic fibrosis.

Nationwide Trends in Acute and Chronic Pancreatitis Among Privately Insured Children and Non-Elderly Adults in the United States, 2007-2014.

BACKGROUND & AIMS: Epidemiologic analyses of acute pancreatitis (AP) and chronic pancreatitis (CP) provide insight into causes and strategies for prevention and affect allocation of resources to its study and treatment. We sought to determine current and accurate incidences of AP and CP, along with the prevalence of CP, in children and adults in the United States. METHODS: We collected data from the Truven MarketScan Research Databases of commercial inpatient and outpatient insurance claims in the United States from 2007 through 2014 (patients 0-64 years old). We calculated the incidences of AP and CP and prevalence of CP based on International Classification of Diseases, 9th Revision diagnosis codes. Children were defined as 18 years or younger and adults as 19 to 64 years old. RESULTS: The incidence of pediatric AP was stable from 2007 through 2014, remaining at 12.3/100,000 persons in 2014. Meanwhile, the incidence for adult AP decreased from 123.7/100,000 persons in 2007 to 111.2/100,000 persons in 2014. The incidence of CP decreased over time in children (2.2/100,000 persons in 2007 to 1.9/100,000 persons in 2014) and adults (31.7/100,000 persons in 2007 to 24.7/100,000 persons in 2014). The prevalences of pediatric and adult CP were 5.8/100,000 persons and 91.9/100,000 persons, respectively, in 2014. Incidences of AP and CP increased with age. We found little change in incidence during the first decade of life but linear increases starting in the second decade. CONCLUSIONS: We performed a comprehensive epidemiologic analysis of privately insured, non-elderly adults and children with AP and CP in the United States. Changes in gallstone formation, smoking, and alcohol consumption, along with advances in pancreatitis management, may be responsible for the stabilization and even decrease in the incidences of AP and CP.

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.

New Algorithm for the Integration of Ultrasound Into Cystic Fibrosis Liver Disease Screening.

OBJECTIVES: Liver nodularity occurs across the spectrum of cystic fibrosis liver disease (CFLD), from regenerative nodules to cirrhosis, and can occur without liver enzyme abnormalities. Our aims were to determine if incorporating abdominal ultrasound (US) with annual laboratory testing improves the detection of CFLD and establish CF-specific thresholds for liver screening labs. METHODS: CF patients at least 6 years old who were exocrine pancreatic-insufficient had an US with Doppler and shear wave elastography. Patients were divided into Normal, Echogenic, or Nodular groups, based on US findings. Results were compared with aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, AST to platelet ratio index (APRI), Fibrosis 4 (FIB-4), and gamma-glutamyl transferase (GGT) to platelet ratio (GPR). Receiver operator curve, sensitivity, specificity, positive predictive value, negative predictive value, and optimal cut-off with Youden Index were calculated. RESULTS: From 82 patients, incorporation of US identified more nodular livers than using labs alone. The Nodular group had significantly greater median AST (44), ALT (48), GGT (46), APRI (0.619), FIB-4 (0.286), GPR (1.431). Optimal cut-offs to detect liver nodularity in CF were AST >33, ALT >45, GGT >21, Platelets <230, APRI >0.367, FIB-4 >0.222, GPR >0.682. Using GGT, APRI, and GPR, we generated an algorithm to direct the use of US in CFLD screening. CONCLUSIONS: Using modified serum lab thresholds, addition of liver fibrosis indices, and/or abdominal US can increase detection of liver nodularity in CF. A combination of GGT, GPR, and APRI can help direct which CF children should undergo US evaluation. These tools may improve earlier identification of fibrosis and/or cirrhosis in CF patients.

Management of Acute Pancreatitis in the Pediatric Population: A Clinical Report From the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas Committee.

BACKGROUND: Although the incidence of acute pancreatitis (AP) in children is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed. METHODS: The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas committee performed a MEDLINE review using several preselected key terms relating to management considerations in adult and pediatric AP. The literature was summarized, quality of evidence reviewed, and statements of recommendations developed. The authorship met to discuss the evidence, statements, and voted on recommendations. A consensus of at least 75% was required to approve a recommendation. RESULTS: The diagnosis of pediatric AP should follow the published INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE definitions (by meeting at least 2 out of 3 criteria: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values ≥3 times upper limits of normal, (3) imaging findings consistent with AP). Adequate fluid resuscitation with crystalloid appears key especially within the first 24 hours. Analgesia may include opioid medications when opioid-sparing measures are inadequate. Pulmonary, cardiovascular, and renal status should be closely monitored particularly within the first 48 hours. Enteral nutrition should be started as early as tolerated, whether through oral, gastric, or jejunal route. Little evidence supports the use of prophylactic antibiotics, antioxidants, probiotics, and protease inhibitors. Esophago-gastro-duodenoscopy, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography have limited roles in diagnosis and management. Children should be carefully followed for development of early or late complications and recurrent attacks of AP. CONCLUSIONS: This clinical report represents the first English-language recommendations for the management of pediatric AP. Future aims should include prospective multicenter pediatric studies to further validate these recommendations and optimize care for children with AP.