A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon

Carlyle, Brent E.; Borowitz, Drucy; Glick, Philip L.

doi:10.1016/j.jpedsurg.2012.02.019

Cited by 123 publications

(112 citation statements)

References 57 publications

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“…We found that, in comparison with WT, intracellular granule expansion, intracellular ectopic granule location, and exocytosis of partially decondensated mucus characterized Cftr-KO goblet cells. The observed anchoring of partially decondensated mucus to the goblet cell greatly increased the surface area of mucosal contact in the formation of obstructing impactions (79)(80)(81), sequestered secreted antimicrobials/trefoil factors (2), and impeded nutrient access (82) at the intestinal epithelium. Extrapolated to the CF airways, mucus retention by goblet cells may be the cellular basis for impaired mucus detachment from submucosal gland ducts that is responsible for deficient mucociliary transport in the CF pig model (30).…”

Section: Discussionmentioning

confidence: 99%

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Liu¹,

Walker²,

Ootani³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Liu¹,

Walker²,

Ootani³

et al. 2015

J. Clin. Invest.

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“…The following scoring system was age of wild-type CFTR transcripts to a clinical phenotype rather than solely to an electrophysiological assay; (d) examining this relationship in CFTR-null pigs has the advantage that potential variations in processing of CFTR-ΔF508 do not introduce a confounding variable. Caveats include the following: (a) we focused on CFTR function in the ileum since the meconium ileus obstruction most commonly occurs in that intestinal segment (47); however, because the in utero pathogenesis of meconium ileus is unknown, it remains possible that CFTR function in other portions of the intestine might be more important for meconium ileus; (b) our estimates are derived from CFTR -/-pigs and not humans with CF; although the porcine meconium ileus phenotype is very similar to that observed in humans, its penetrance is much greater than in humans (100% vs. 15%-20%) (14)(15)(16)19); thus, intestinal anatomy, physiology, or genetic modifiers might differ in pigs and humans and thereby alter the relationship between CFTR function and meconium ileus severity; (c) our studies were conducted on newborn tissue, and we cannot say how much CFTR function is required during intestinal development.…”

Section: Cftr Expression In the Intestine Is Sufficient To Rescue Mecmentioning

confidence: 95%

“…Not knowing whether this transgenic approach would work, we decided to enhance the likelihood of correcting meconium ileus by treating the majority of animals with Gastrografin enemas after birth. This strategy is used to treat meconium ileus in human newborns with CF (18,19), but failed to relieve the intestinal obstruction in CF pigs. The response to the enema was variable among litters.…”

Section: Generation Of Cftr -/-;Tgfabp>pcftr Pigsmentioning

confidence: 99%

“…The meconium ileus in CF pigs would be lethal if not corrected soon after birth. In some cases, Gastrografin enemas can relieve meconium ileus obstruction and result in avoidance of surgical correction in newborn babies with CF (18,19). However, attempts to nonsurgically correct the intestinal obstruction in CF pigs were unsuccessful, in part due to the atretic intestinal segments.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

Stoltz¹,

Rokhlina²,

Ernst³

et al. 2013

J. Clin. Invest.

115

127

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Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR -/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.

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“…1 Affected newborns often present with severe bowel obstruction caused by inspissated mucous and meconium occluding the mid or distal small bowel. Resolution of the ileal obstruction requires extensive treatment, including rectal infusion of gastrografin and/or enema under fluoroscopic control, as well as additional saline/acetylcysteine enemas.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

Dupuis

Keenan

Ooi

et al. 2016

Genetics in Medicine

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Rationale: Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype-phenotype correlation for severe mutations.Method: MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). Results:The prevalence of MI varied among the different registries (13-21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying "severe" CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04).Conclusions: MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes.

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A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon

Cited by 123 publications

References 57 publications

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

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