Immunoreactive trypsinogen levels in newborn screened infants with an inconclusive diagnosis of cystic fibrosis.

Background: Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID).

Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population.

Previous reports of lung function in cystic fibrosis (CF) patients with liver disease have shown worse, similar, or even better forced expiratory volume in 1 second (FEV1), compared to CF patients without liver disease. Varying definitions of CF liver disease likely contribute to these inconsistent relationships reported between CF lung function and liver disease. We retrospectively evaluated spirometric data in 179 subjects (62% male; 58% Phe508del homozygous) with severe CF liver disease (CFLD; defined by presence of portal hypertension due to cirrhosis).

Diagnosis and management of pancreatic exocrine insufficiency (PEI) in primary care: consensus guidance of a Canadian expert panel.

Background: Pancreatic exocrine insufficiency (PEI) results in maldigestion due to inadequate activity of pancreatic enzymes in the small bowel. PEI can arise from a variety of medical conditions that reduce enzyme synthesis within the pancreatic parenchyma or from secondary factors that may occur despite optimal parenchymal function, such as pancreatic duct obstruction or impaired or poorly synchronized enzyme release.

Purpose: To provide practical guidance for primary care physicians managing patients who are at risk of PEI or who present with symptoms of PEI.

Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity.

Rationale: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known.

Objectives: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing "in vivo" CF airway epithelial gene expression complemented with genome-wide association study (GWAS) data.

Therapeutic Endoscopic Retrograde Cholangiopancreatography in Pediatric Patients With Acute Recurrent and Chronic Pancreatitis: Data From the INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) Study.

Objective: The aim of this study was to characterize utilization and benefit of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP).

Methods: From August 2012 to February 2015, 301 children with ARP or CP were enrolled in the INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) study. Physicians reported utilization and benefit of therapeutic ERCP at enrollment.

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A.

Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE.

Importance: Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood.

Objective: To characterize and identify risk factors associated with ARP and CP in childhood.

Design, Setting, And Participants: A multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium.

Features of Severe Liver Disease With Portal Hypertension in Patients With Cystic Fibrosis.

Background & Aims: Liver disease is the third leading cause of death in patients with cystic fibrosis (CF), but features of patients with CF, severe liver disease, and portal hypertension have not been characterized fully.

Methods: We performed a retrospective analysis of data from 561 patients with CF (63% male, 99% with pancreatic insufficiency), liver disease (hepatic parenchymal abnormalities consistent with cirrhosis, confirmed by imaging), and portal hypertension (esophageal varices, portosystemic collaterals, or splenomegaly), with no alternate causes of liver disease. All patients were enrolled in the Genetic Modifier Study of Severe CF Liver Disease at 76 international centers, from January 1999 through July 2013.

Cystic fibrosis from the gastroenterologist's perspective.

Cystic fibrosis is a life-limiting, recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Increased survival outcomes and the multisystem nature of the disease, including the involvement of hepatobiliary and gastrointestinal tracts, now require the need for more extensive knowledge and expertise in cystic fibrosis among gastroenterologists. Manifestations are either a direct consequence of the primary defect in cystic fibrosis or a secondary complication of the disease or therapy.

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease.

A Joint Location-Scale Test Improves Power to Detect Associated SNPs, Gene Sets, and Pathways.

Gene-based, pathway, and other multivariate association methods are motivated by the possibility of GxG and GxE interactions; however, accounting for such interactions is limited by the challenges associated with adequate modeling information. Here we propose an easy-to-implement joint location-scale (JLS) association testing framework for single-variant and multivariate analysis that accounts for interactions without explicitly modeling them. We apply the JLS method to a gene-set analysis of cystic fibrosis (CF) lung disease, which is influenced by multiple environmental and genetic factors.

In Vivo Senescence in the Sbds-Deficient Murine Pancreas: Cell-Type Specific Consequences of Translation Insufficiency.

Genetic models of ribosome dysfunction show selective organ failure, highlighting a gap in our understanding of cell-type specific responses to translation insufficiency. Translation defects underlie a growing list of inherited and acquired cancer-predisposition syndromes referred to as ribosomopathies. We sought to identify molecular mechanisms underlying organ failure in a recessive ribosomopathy, with particular emphasis on the pancreas, an organ with a high and reiterative requirement for protein synthesis.

Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis.

Objectives: To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal cystic fibrosis (CF) transmembrane conductance regulator protein, including known CF modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) immunoreactive trypsinogen (IRT) levels.

Study Design: NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of 8 single nucleotide polymorphisms (SNPs) in SLC26A9, SLC6A14, and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT.

Altered intestinal bile salt biotransformation in a cystic fibrosis (Cftr-/-) mouse model with hepato-biliary pathology.

Background: Cftr(-/-tm1Unc) mice develop progressive hepato-biliary pathology. We hypothesize that this liver pathology is related to alterations in biliary bile hydrophobicity and bile salt metabolism in Cftr(-/-tm1Unc) mice.

Methods: We determined bile production, biliary and fecal bile salt- and lipid compositions and fecal bacterial composition of C57BL/6J Cftr(-/-tm1Unc) and control mice.

Does integration of various ion channel measurements improve diagnostic performance in cystic fibrosis?

Rationale: The diagnosis of cystic fibrosis (CF) may remain inconclusive despite comprehensive evaluation.

Objectives: Determine whether combined ion channel measurements (C-ICMs) obtained from different end-organ epithelia can help diagnose CF.

Methods: Prospective enrollment of (1) a training sample of 156 non-CF subjects and 107 patients with CF, and (2) a validation cohort of 202 patients with single-organ CF-like phenotypes.

Evidence for a causal relationship between early exocrine pancreatic disease and cystic fibrosis-related diabetes: a Mendelian randomization study.

Circulating immunoreactive trypsinogen (IRT), a biomarker of exocrine pancreatic disease in cystic fibrosis (CF), is elevated in most CF newborns. In those with severe CF transmembrane conductance regulator (CFTR) genotypes, IRT declines rapidly in the first years of life, reflecting progressive pancreatic damage. Consistent with this progression, a less elevated newborn IRT measure would reflect more severe pancreatic disease, including compromised islet compartments, and potentially increased risk of CF-related diabetes (CFRD).

Simultaneous liver-pancreas transplantation for cystic fibrosis-related liver disease: a multicenter experience.

Background: Diabetes is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). While liver transplantation is well established for CF-related liver disease (CFLD), the role of simultaneous liver-pancreas transplantation is less understood.

Methods: We polled 81 pediatric transplantation centers to identify and characterize subjects who had undergone simultaneous liver-pancreas transplantation and obtain opinions about this procedure in CFLD.

Abdominal pain in adults with cystic fibrosis.

Abdominal pain is a common symptom in individuals with cystic fibrosis (CF). As prognosis has improved, CF has changed from a pediatric disease to the current situation wherein most people with CF are adults. With improved survival, the spectrum of pathologies causing abdominal pain in CF has shifted.

Does extensive genotyping and nasal potential difference testing clarify the diagnosis of cystic fibrosis among patients with single-organ manifestations of cystic fibrosis?

Background: The phenotypic spectrum of cystic fibrosis (CF) has expanded to include patients affected by single-organ diseases. Extensive genotyping and nasal potential difference (NPD) testing have been proposed to assist in the diagnosis of CF when sweat testing is inconclusive. However, the diagnostic yield of extensive genotyping and NPD and the concordance between NPD and the sweat test have not been carefully evaluated.