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Diagnostics (Basel, Switzerland) Jun 2024The early management of neonates with meconium ileus (MI) and cystic fibrosis (CF) is highly variable across countries and is not standardized. We conducted a systematic... (Review)
Review
The early management of neonates with meconium ileus (MI) and cystic fibrosis (CF) is highly variable across countries and is not standardized. We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The protocol was registered in PROSPERO (CRD42024522838). Studies from three providers of academic search engines were checked for inclusion criteria, using the following search terms: meconium ileus AND cystic fibrosis OR mucoviscidosis. Regarding the patient population studied, the inclusion criteria were defined using our predefined PICOT framework: studies on neonates with simple or complicated meconium which were confirmed to have cystic fibrosis and were conservatively managed or surgically treated. Results: A total of 566 publications from the last 10 years were verified by the authors of this review to find the most recent and relevant data, and only 8 met the inclusion criteria. Prenatally diagnosed meconium pseudocysts, bowel dilation, and ascites on ultrasound are predictors of neonatal surgery and risk factor for negative 12-month clinical outcomes in MI-CF newborns. For simple MI, conservative treatment with hypertonic solutions enemas can be effective in more than 25% of cases. If repeated enemas fail to disimpact the bowels, the Bishop-Koop stoma is a safe option. No comprehensive research has been conducted so far to determine the ideal surgical protocol for complicated MI. We only found three studies that reported the types of stomas performed and another study comparing the outcomes of patients depending on the surgical management; the conclusions are contradictory especially since the number of cases analyzed in each study was small. Between 18% and 38% of patients with complicated MI will require reoperation for various complications and the mortality rate varies between 0% and 8%. Conclusion: This study reveals a lack of strong data to support management decisions, unequivocally shows that the care of infants with MI is not standardized, and suggests a great need for international collaborative studies.
PubMed: 38893705
DOI: 10.3390/diagnostics14111179 -
Radiographics : a Review Publication of... Aug 2023Radiologic evaluation of neonatal bowel obstruction is challenging owing to the overlapping clinical features and imaging appearances of the most common differential...
Radiologic evaluation of neonatal bowel obstruction is challenging owing to the overlapping clinical features and imaging appearances of the most common differential diagnoses. The key to providing an appropriate differential diagnosis comes from a combination of the patient's gestational age, clinical features, and imaging findings. While assessment of radiographs can confirm bowel obstruction and indicate whether it is likely proximal or distal, additional findings at upper or lower gastrointestinal contrast study together with use of US are important in providing an appropriate differential diagnosis. The authors provide an in-depth assessment of the appearances of the most common differential diagnoses of proximal and distal neonatal bowel obstruction at abdominal radiography and upper and lower gastrointestinal contrast studies. These are divided into imaging patterns and their associated differential diagnoses on the basis of abdominal radiographic findings. These findings include esophageal atresia variants including the "single bubble," "double bubble," and "triple bubble" and distal bowel obstruction involving the small and large bowel. Entities discussed include esophageal atresia, hypertrophic pyloric stenosis, pyloric atresia, duodenal atresia, duodenal web, malrotation with midgut volvulus, jejunal atresia, ileal atresia, meconium ileus, segmental volvulus, internal hernia, colonic atresia, Hirschsprung disease, and functional immaturity of the large bowel. The authors include the advantages of abdominal US in this algorithm, particularly for hypertrophic pyloric stenosis, duodenal web, malrotation with midgut volvulus, and segmental volvulus. RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.
Topics: Infant, Newborn; Humans; Intestinal Volvulus; Esophageal Atresia; Pyloric Stenosis, Hypertrophic; Intestinal Obstruction; Duodenal Obstruction; Digestive System Abnormalities; Radiography, Abdominal; Duodenal Diseases
PubMed: 37471246
DOI: 10.1148/rg.230035 -
Channels (Austin, Tex.) Dec 2023SLC26A9 is one out of 11 proteins that belong to the SLC26A family of anion transporters. Apart from expression in the gastrointestinal tract, SLC26A9 is also found in... (Review)
Review
SLC26A9 is one out of 11 proteins that belong to the SLC26A family of anion transporters. Apart from expression in the gastrointestinal tract, SLC26A9 is also found in the respiratory system, in male tissues and in the skin. SLC26A9 has gained attention because of its modifier role in the gastrointestinal manifestation of cystic fibrosis (CF). SLC26A9 appears to have an impact on the extent of intestinal obstruction caused by meconium ileus. SLC26A9 supports duodenal bicarbonate secretion, but was assumed to provide a basal Cl- secretory pathway in airways. However, recent results show that basal airway Cl- secretion is due to cystic fibrosis conductance regulator (CFTR), while SLC26A9 may rather secrete HCO-, thereby maintaining proper airway surface liquid (ASL) pH. Moreover, SLC26A9 does not secrete but probably supports reabsorption of fluid particularly in the alveolar space, which explains early death by neonatal distress in Slc26a9-knockout animals. While the novel SLC26A9 inhibitor S9-A13 helped to unmask the role of SLC26A9 in the airways, it also provided evidence for an additional role in acid secretion by gastric parietal cells. Here we discuss recent data on the function of SLC26A9 in airways and gut, and how S9-A13 may be useful in unraveling the physiological role of SLC26A9.
Topics: Animals; Biological Transport; Cystic Fibrosis; Intestines; Respiratory System; Sulfate Transporters; Antiporters
PubMed: 36866602
DOI: 10.1080/19336950.2023.2186434 -
World Journal of Gastroenterology Sep 2023Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious... (Review)
Review
Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung's disease (HD), meconium ileus due to Cystic Fibrosis, The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow's milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities.
Topics: Animals; Cattle; Female; Infant; Pregnancy; Humans; Milk Hypersensitivity; Constipation; Biopsy; Diarrhea; Hirschsprung Disease
PubMed: 37731998
DOI: 10.3748/wjg.v29.i33.4920 -
Journal of Cystic Fibrosis : Official... Nov 2023Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR)... (Review)
Review
Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR) mutations and pancreatic insufficiency (PI). D1152H is a class IV mutation that corresponds with a milder CF phenotype and pancreatic sufficiency (PS). We present the case of an infant with G542X/D1152H mutations and MI who required surgical intervention with small bowel resection. The sweat testing was normal, and this child presently remains PS, however at age 5 continues to experience short gut syndrome and failure to thrive. Eight cases were identified in the CF Registry and seven cases in the literature describing patients with D1152H and echogenic bowel (EB) or MI. Our case highlights the importance of CFTR gene sequencing in infants with EB or MI and sweat testing not suggestive of CF. It is our practice to perform full CFTR gene sequencing for infants who present with MI, recognizing protocols for newborn screening across the United States vary. Increased awareness of D1152H association with PS may also well inform both prenatal and postnatal genetic counseling.
Topics: Infant, Newborn; Child; Infant; Female; Pregnancy; Humans; Child, Preschool; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis; Meconium Ileus; Mutation; Phenotype; Ileus; Meconium
PubMed: 37423798
DOI: 10.1016/j.jcf.2023.02.002 -
Expert Review of Respiratory Medicine 2023Gastrointestinal (GI)-related symptoms, complications, and comorbidities in cystic fibrosis (CF) are common and research to reduce their burden is a priority for the CF... (Review)
Review
INTRODUCTION
Gastrointestinal (GI)-related symptoms, complications, and comorbidities in cystic fibrosis (CF) are common and research to reduce their burden is a priority for the CF community. To enable future research, this review aimed to summarize the range of GI symptoms, complications and comorbidities seen in CF, the underlying pathophysiology, and treatments.
AREAS COVERED
This was a rapid systematic review undertaken using the recommendations from the Cochrane Rapid Reviews Methods Group. We searched databases including PubMed, Embase, Medline and the Cochrane database and identified those studies reporting GI-related symptoms, complications, or comorbidities in CF or their treatment. Our searches identified 2,930 studies and a total 119 studies met our inclusion criteria. Where a prevalence could be determined, GI symptoms were reported in 33.7% of study participants. The range of symptoms reported was broad and the highest median prevalence included flatulence (43.5%), bloating and abdominal distension (36%), and fatty stool (36%). Meconium ileus was reported in 12% and distal intestinal obstruction syndrome in 8.5.
EXPERT OPINION
GI-related symptoms, complications, and comorbidities in CF are common. More consistent characterization and recording of these symptoms in clinical studies may help achieve the priority of reducing the burden of GI disease in CF.
Topics: Humans; Cystic Fibrosis; Intestinal Obstruction; Comorbidity; Prevalence
PubMed: 37345513
DOI: 10.1080/17476348.2023.2228194 -
Pediatric Pulmonology Sep 2023Tracheobronchomalacia (TBM) is estimated to be present in 1 in 2100 children. Previous reports suggest the prevalence is higher in children with cystic fibrosis (CF)....
BACKGROUND
Tracheobronchomalacia (TBM) is estimated to be present in 1 in 2100 children. Previous reports suggest the prevalence is higher in children with cystic fibrosis (CF). This has clinical implications with potential to influence airway clearance and lung health.
AIM
To determine the prevalence and clinical associations of TBM in Western Australian children with CF.
METHODS
Children with CF born between 2001 and 2016 were included. Operation reports from bronchoscopies performed until the age of 4 were retrospectively reviewed. Data were collected on the presence, persistence defined as a repeat diagnosis, and severity of TBM. Data on genotype, pancreatic status, and symptoms at CF diagnosis were extracted from the medical record. Associations between categorical variables were compared using χ and Fisher's exact test.
RESULTS
Of 167 children (79 male), 68 (41%) were diagnosed with TBM at least once, with TBM persistent in 37 (22%) and severe in 31 (19%). TBM was significantly associated with pancreatic insufficiency (χ = 7.874, p < 0.05, odds ratio [OR] 3.4), delta F508 gene mutation (χ = 6.489, p < 0.05, OR 2.3), and a presentation of meconium ileus (χ = 8.615, p < 0.05, OR 5.0). Severe malacia was less likley in females (χ = 4.523, p < 0.05, OR 0.42) . No significant relationship was found with respiratory symptoms at the time of CF diagnosis (χ = 0.742, p = 0.39).
CONCLUSIONS
TBM was common in this group of children under the age of 4 with CF. A high index of suspicion for airway malacia should be considered in children with CF, particularly those who present with meconium ileus and have gastrointestinal symptoms at diagnosis.
Topics: Female; Humans; Male; Child; Cystic Fibrosis; Meconium Ileus; Prevalence; Retrospective Studies; Australia; Cystic Fibrosis Transmembrane Conductance Regulator
PubMed: 37294078
DOI: 10.1002/ppul.26550 -
RSC Medicinal Chemistry Nov 2023A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus,...
A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus, distal intestinal obstruction syndrome (DIOS) and constipation. Since CFTR modulators have minimal effects on gastrointestinal symptoms, there is an unmet need for novel treatments for CF-associated gastrointestinal disorders. Meconium ileus and DIOS mainly affect the ileum (distal small intestine). SLC26A6 (putative anion transporter 1, PAT1) is a Cl/HCO exchanger at the luminal membrane of small intestinal epithelial cells which facilitates Cl and fluid absorption. We recently identified first-in-class PAT1 inhibitors by high-throughput screening. Isoxazolopyrimidine PAT1-A01 was a hit compound, which had low potency (IC 5.2 μM) for SLC26A6 inhibition precluding further preclinical development. Here we performed structure-activity relationship studies to optimize isoxazolopyrimidine SLC26A6 inhibitors and tested a potent inhibitor in mouse models of intestinal fluid absorption. Structure-activity studies of 377 isoxazolopyrimidine analogs identified PAT1-A0030 (ethyl 4-(benzyl(methyl)amino)-3-methylisoxazolo[5,4-]pyrimidine-6-carboxylate) as the most potent SLC26A6 inhibitor with a 1.0 μM IC. Selectivity studies showed that PAT1-A030 has no activity on relevant ion transporters/channels (SLC26A3, SLC26A4, SLC26A9, CFTR, TMEM16A). In a closed-loop model of intestinal fluid absorption, intraluminal PAT1-A0030 treatment inhibited fluid absorption in the ileum of wild-type and CF mice () with >90% prevention of a decrease in loop fluid volume and loop weight/length ratio at 30 minutes. These results suggest that SLC26A6 is the key transporter mediating Cl and fluid absorption in the ileum and SLC26A6 inhibitors are novel drug candidates for treatment of CF-associated small intestinal disorders.
PubMed: 37974969
DOI: 10.1039/d3md00302g -
Nutrition in Clinical Practice :... Apr 2024Cystic fibrosis (CF) is a progressive, genetic, multi-organ disease affecting the respiratory, digestive, endocrine, and reproductive systems. CF can affect any aspect... (Review)
Review
Cystic fibrosis (CF) is a progressive, genetic, multi-organ disease affecting the respiratory, digestive, endocrine, and reproductive systems. CF can affect any aspect of the gastrointestinal (GI) tract, including the esophagus, stomach, small intestine, colon, pancreas, liver, and gall bladder. GI pathophysiology associated with CF results from CF membrane conductance regulator (CFTR) dysfunction. The majority of people with CF (pwCF) experience exocrine pancreatic insufficiency resulting in malabsorption of nutrients and malnutrition. Additionally, other factors can cause or worsen fat malabsorption, including the potential for short gut syndrome with a history of meconium ileus, hepatobiliary diseases, and disrupted intraluminal factors, such as inadequate bile salts, abnormal pH, intestinal microbiome changes, and small intestinal bacterial overgrowth. Signs and symptoms associated with fat malabsorption, such as abdominal pain, bloating, malodorous flatus, gastroesophageal reflux, nausea, anorexia, steatorrhea, constipation, and distal intestinal obstruction syndrome, are seen in pwCF despite the use of pancreatic enzyme replacement therapy. Given the association of poor nutrition status with lung function decline and increased mortality, aggressive nutrition support is essential in CF care to optimize growth in children and to achieve and maintain a healthy body mass index in adults. The introduction of highly effective CFTR modulator therapy and other advances in CF care have profoundly changed the course of CF management. However, GI symptoms in some pwCF may persist. The use of current knowledge of the pathophysiology of the CF GI tract as well as appropriate, individualized management of GI symptoms continue to be integral components of care for pwCF.
Topics: Child; Adult; Humans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Malabsorption Syndromes; Gastrointestinal Diseases; Malnutrition
PubMed: 38429959
DOI: 10.1002/ncp.11122