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Cystic fibrosis ( CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane regulatory protein (CFTR) gene. The CFTR gene encodes an ion channel with the same name.
The CFTR protein is expressed throughout the gastrointestinal (GI) tract, including the pancreas, intestine, and bile ducts, and primarily conducts chloride and/or bicarbonate ions.
Dysfunctional CFTR protein results in abnormal electrolyte composition, altered pH, and thickened mucus in the GI, pulmonary, reproductive, and other organ systems. 1
Knowledge of patients’ CFTR gene mutations may help predict the severity of their disease and response to CFTR-modulating therapy. More than 2,000 CFTR gene mutations have been described and have typically been divided into 6 categories based on their impact on CFTR mRNA and/or protein synthesis, function, or stability.
Class I, II, and III mutations are considered severe and result in an absent or nonfunctional CFTR protein. The most common CF mutation, F508del, present in ~90% of non-Hispanic white patients with CF in the United States, is classified as a class II defect.
Class IV, V and VI mutations are residual function mutations, which result in a partially functional CFTR protein on the cell surface, and are typically associated with a milder course of disease characterized by a later onset of the disease, a slower deterioration of lung function, and preserved pancreatic function.
Since the advent of CFTR-modulating therapy, an expanded classification scheme has been proposed to include class VII, characterized by large deletions and frameshift mutations with limited therapeutic options. 2
Diagnosis
In the United States, the diagnosis of CF is commonly, but not exclusively, made through neonatal screening (NC).
The importance of timely diagnosis cannot be underestimated. Early diagnosis through NC leads to earlier intervention, which has been associated with better pulmonary and nutritional outcomes. 3,4 This is especially relevant given the spectacular advances made in CFTR-modulating therapy, which, although not currently approved for newborns, holds great promise for preventing and potentially reversing gastrointestinal pathology when initiated early.
In the United States, individual state CN protocols vary, so it is important to be familiar with your state’s approach. Generally, CN protocols use 2 serial assays, serum immunoreactive trypsinogen (TIS), which is often elevated in infants with CF (due to pancreatic damage in utero), and DNA analysis for CFTR mutations.
The number of CFTR gene mutations and/or the use of full CFTR sequencing varies by state.
Of note, those with milder mutations and without early pancreatic damage may go undetected in CN due to a normal TIS. If the CN is positive, the next step is to proceed with a sweat chloride test , which is performed on infants older than 2 weeks of age and weighing more than 2 kg. 5
- An abnormal sweat chloride concentration greater than or equal to 60 mmol/L is diagnostic of CF.
- A sweat chloride concentration of less than 30 mmol/L is normal .
Infants with abnormal sweat chloride findings require genetic testing to confirm 2 disease-causing mutations in CFTR. Children with indeterminate sweat chloride value (30–59 mmol/L) can be classified as having CF-related metabolic syndrome. 6
In circumstances where the CF diagnosis is unclear, due to concern about false negatives/positives on the sweat test or the inability to repeatedly obtain sufficient sweat, alternative CFTR functional testing may be performed; however, these capabilities are not uniformly available at all centers.
An alternative test of CFTR function may involve obtaining nasal or intestinal epithelial cells (using nasal brushings or rectal suction biopsies in neonates) for short-circuit current measurements or organoid edema assays.
Nasal potential difference measurements and other sweat testing modalities can be performed in older children, but are not performed in infants.
In the prenatal period, carrier screening should be offered to all couples planning a pregnancy and to pregnant women.
Risk factors include personal or family history of CF, racial ethnicity (non-Hispanic white individuals and individuals of Ashkenazi Jewish ancestry), and certain prenatal ultrasound findings, such as echogenic bowel in the second trimester, suggesting meconium ileus.
Carrier screening includes a panel of 23 of the most common mutations found in individuals in the United States. CFTR gene sequencing can also be performed, but is typically reserved for people with a family history of CF with an unknown genetic mutation and negative carrier screening.
There are limitations to these diagnostic tools. First, genetic tests used in NC and carrier screening typically include 23 disease-causing variants, reflecting the most common variants in individuals of Northern European ancestry.
Carrier detection rates by racial/ethnic group for this panel in the United States vary: Ashkenazi Jewish ancestry (94%), non-Hispanic white (88%), Hispanic white (72%), black (64%), and Asian -Americans (49%). 7
Individuals classified as Black/African American, American Indian/Alaska Native, Asian or Hispanic, or other racial groups have different distributions of CFTR variants that may go undetected in CN or carrier screening, resulting in delays in detection. intervention and racial disparities compared to those categorized as white and non-Hispanic. 8.9
In these groups with less characterized mutations, CFTR gene sequencing and multiple ligand-dependent probe amplification may be necessary to identify large deletions and duplications. 10 Additionally, detection of TIS in CN may be changing due to the increasing use of modulatory therapy in pregnant women with CF.
Given the limitations of screening and the possibility of false-negative results, it is vital to recognize CF manifestations as early as possible to optimize long-term nutritional and pulmonary outcomes. 6,11,12 Gastrointestinal complications are usually the first manifestation of the disease and can be divided into 4 categories: gastrointestinal, hepatobiliary, pancreatic and nutritional.
Gastrointestinal complications
> Gastroesophageal reflux disease
Gastroesophageal reflux ( GER) is the physiological passage of gastric contents into the esophagus. GER is a normal and self-limiting process, unlike gastroesophageal reflux disease (GERD), in which reflux is associated with complications such as esophagitis, respiratory compromise, or weight loss.
The incidence of GERD in infants with CF is reported to be approximately 20%. 13
The reasons why infants with CF develop reflux are not well known, but are probably related to lower basal lower esophageal sphincter pressure, transient relaxations of the lower esophageal sphincter, delayed gastric emptying, and increased pressure gradient. gastroesophageal due to lower inspiratory intrathoracic pressure. 14
Infants with GERD may present with vomiting, irritability, and cough, and in cases of GERD, aspiration, respiratory distress, and weight loss.
The diagnosis of GERD is usually based on clinical symptoms, but complementary tools include serial imaging of the upper gastrointestinal tract, multichannel intraluminal impedance and pH (IIM-pH) testing, and esophagogastroduodenoscopy (EGD).
The upper gastrointestinal series is used to evaluate esophageal and gastric anatomy and to evaluate for the presence of tracheoesophageal fistula, achalasia, hiatal hernia, and malrotation, which may present similarly.
The IIM-pH test is reserved for cases of GERD that are refractory to lifestyle changes and gastric acid suppression.
It can detect reflux of acidic and non-acidic gastric contents into the esophagus and correlate with symptoms. EGD is used to evaluate esophagitis and other alternative causes. Both EGD and IIM-pH testing should be performed in consultation with pediatric gastroenterologists.
For patients with CF and GERD, treatment does not differ significantly from GERD recommendations for infants without CF, and primarily involves dietary changes, followed by gastric acid suppression. fifteen
Dietary recommendations include eating small, frequent meals, trying thickened feeds, and eliminating cow’s milk protein.
Positional therapy, such as head elevation or lateral or prone position, is not recommended to treat GERD in sleeping infants due to the risk of sudden infant death syndrome.
For babies with CF, postural drainage involves positioning babies so that mucus can be removed from the airways by gravity and is used for lung clearance until they can participate in their own respiratory management. However, there is an associated risk of GER with this technique.
Freitas et al. 16 compared 2 randomized controlled studies comparing 2 postural drainage regimens for GER in infants and young children with CF. The authors found that the 30-degree head-up tilt regimen was associated with fewer episodes of GER and long-term respiratory complications. 16
For babies who do not respond to lifestyle or diet change, gastric acid suppression may be considered.
Histamine 2 receptor antagonists or proton pump inhibitors (PPIs) can be used.
PPIs have superior efficacy in lowering gastric fluid pH, but have also been associated with more potential adverse effects, including an increased incidence of pulmonary and Clostridium difficile infections and decreased absorption of iron, vitamin B 12 , and calcium. 17,18,19 Additionally, the use of gastric acid suppression may not reduce distress, vomiting, regurgitation, or other symptoms associated with GERD in infants. 15 Therefore, its use requires careful consideration and discontinuation once possible.
Finally, for those patients who have failed dietary and medical treatment and are at risk for significant disease related to GERD complications, fundoplication may be considered.
However, fundoplication has been associated with significant complications including gas distention, early satiety/pain, dysphagia, retching, dumping syndrome, and worsening risk of aspiration from esophageal stasis and sheath slippage/unwrapping, and a subset of Patients may even develop GERD symptoms after surgery. 15,20 Therefore, the benefits and risks of surgery should be carefully weighed in consultation with a pediatric gastroenterologist.
> Meconium ileus
Meconium ileus (MI) is a neonatal cause of small bowel obstruction and may be one of the first manifestations of CF, with an incidence of 20%. 21 Previously a major cause of morbidity and mortality, with greater understanding and recognition of this disease, current survival rates are greater than 80%. twenty-one
Knowledge of the pathophysiology of MI has been acquired through animal models, especially with inactivation of ferret and pig CFTR. 21,22 In normal mucogenesis, mucins are contained in a matrix around calcium ions. Upon exocytosis into the intestine, bicarbonate chelates calcium ions, causing mucins to expand rapidly. Together with chloride and water, the complex forms a normal, well-hydrated mucus.
The abnormal CFTR protein causes altered secretion of chloride and bicarbonate, creating an acidic and dehydrated environment. The compressed matrix is not sufficiently disturbed, leading to the formation of a dense, dehydrated mucus that remains attached to the epithelial cells. The acidic lumen also elevates stool albumin and mineral and carbohydrate content, which combine with thick mucus to form viscous meconium and lead to intestinal obstruction. 21,22 This process develops in the uterus.
Patients with CFTR class I to III mutations (F508del, G542X, W1282X, R553X, and G551D) have an increased risk of developing MI. 23 Patients with 2 copies of F508del mutations have a 24.9% risk of developing MI, F508del combined with another mutation has a risk of 16.9%, and 2 other mutations has a risk of 12.5%. 24 There is greater concordance in monozygotic twins. In families in which one child has MI, the chance of a subsequent child with CF developing MI is higher than expected, suggesting the presence of modifying genes. 25
The IM can be divided into simple and complex forms. In simple MI, the terminal ileum is obstructed by viscous meconium, causing dilation of the proximal small intestine, which fills with meconium, gas, and fluid. These patients present in the first 48 hours after birth with bilious vomiting, abdominal distention, and failure to pass meconium.
In complex MI, ileal distension produces other complications, such as volvulus, ischemic necrosis, intestinal atresia, and intestinal perforation, which can lead to meconium peritonitis. Patients with peritonitis may present with abdominal pain, fever, and hemodynamic instability. Meconium may also become encapsulated, resulting in giant cystic meconium peritonitis, which may present as a palpable mass on physical examination. It is important to exclude other causes of neonatal obstruction, such as intestinal atresia, meconium plug, and Hirschsprung’s disease, which can be differentiated by imaging. 26
MI can be detected prenatally on second trimester ultrasound and may include hyperechoic masses due to thick meconium in the terminal ileum, dilated bowel, and lack of visualization of the gallbladder. In isolation, these are not specific to IM. A hyperechoic intestine can be seen in Down syndrome, intrauterine growth restriction, cytomegalovirus infection, and normal pregnancy.
Lack of visualization of the gallbladder can also be seen in biliary atresia, omphalocele, diaphragmatic hernia, chromosomal abnormalities, and normal pregnancy. In the presence of suggestive ultrasound findings, the fetus should be followed with ultrasound every 6 weeks at least. 27,28 Intended parents should be offered carrier screening and genetic counseling.
Postnatally, abdominal imaging typically demonstrates dilated intestinal loops with or without air-fluid levels. If there is complete obstruction, there may be no air in the rectum. The “soap bubble” sign may also be observed, which occurs when meconium mixes with swallowed air in the distal small intestine. 26 In a stable infant, a hyperosmotic contrast enema is performed to confirm the diagnosis and usually shows a microcolon due to lack of use of the colon distal to the obstruction in the terminal ileum. twenty-one
For babies with MI, postnatal treatment depends on the patient’s stability and whether the MI is simple or complex. Stable patients with simple MI are treated conservatively with bowel rest, gastric decompression, empirical antibiotic coverage, and gastrografin enemas. After administration of the gastrografin enema, meconium passage can be observed generally within 24 to 48 hours.
Abdominal imaging should be performed every 8 to 12 hours after enema administration to confirm evacuation and exclude perforation. If evacuation is incomplete or if gastrografin does not reach the site of obstruction, an enema may be repeated every 12 to 24 hours as necessary. 22.29
When hyperosmolar gastrografin is used, adequate intravenous hydration with at least 150 mL/kg daily is necessary to avoid resulting hypovolemia and shock and end-organ damage. Another risk includes perforation due to intestinal distension by fluid or direct mucosal injury by contrast medium, which can be reduced by administering the enema under fluoroscopic guidance and avoiding inflation of balloon-tipped catheters. The success rate for simple MI using the gastrografin enema ranges from 36% to 85%. 30 Recent studies have reported lower success rates, probably due to fewer enema attempts before proceeding with surgical management or the use of lower osmolarity enemas.
Surgical management is reserved for patients who fail medical management or in cases of complex MI. The goals of surgery include evacuation of meconium and establishment of intestinal continuity while preserving maximum length of the intestine. Approaches include enterostomy with lavage followed by primary anastomosis and decompression by ostomy creation.
Comparison of these 2 approaches has had varying results. Karimi et al. (30) examined 34 patients treated surgically with MI and compared the rates of complications secondary to resection with primary anastomosis vs. enterostomy. The authors reported the need for surgery in 11 patients with simple MR and 23 with complex MR, of whom 21% with primary anastomosis developed peritonitis while none with enterostomy did. 30
Jawaheer et al. 31 studied 13 children with MI treated with resection and primary anastomosis and found a rate of surgical complications of 31% (anastomotic strictures, adhesive intestinal obstruction, retraction of intra-abdominal drainage). In a previous study by Del Pin et al., 32 the authors found no significant differences in morbidity between surgical approaches.
> Meconium plug syndrome
Meconium plug syndrome is another cause of neonatal intestinal obstruction, but here the thick luminal contents obstruct the colon, unlike the terminal ileum in MI. Meconium plug syndrome is less commonly associated with CF, usually responds to hyperosmolar enemas, and rarely requires surgery. 33
> Invagination
Although intussusception is associated with CF, most cases are uncomplicated, and only 1% of cases require medical treatment. The age distribution is bimodal, with the first peak in childhood and the second occurring at approximately 10 years of age. 34 The most common site of pathology is the ileocolonic portion, which may be due to thick secretions that create a guiding point for telescopic section of intestine.
This is likely to be exacerbated by the altered motility, intestinal thickening, and dilation of the appendix seen in CF. 35 Babies may have colicky pain, nausea, vomiting, and bloody stools.
Examination may reveal a palpable mass in the right quadrant. On ultrasound, the “donut” or “pseudokidney” sign can be observed, which represent the telescopic section of the intestine in transverse and longitudinal views, respectively. The “coiled spring” sign can be seen on contrast enema, which is both diagnostic and therapeutic. 35 In cases where contrast or air enema fails, laparotomy with manual reduction is indicated.
> Dysbiosis
The gut microbiota during childhood shows the greatest degree of variability in the first 2 to 3 years of age, after which it exhibits a more stable adult pattern. Infants have a nearly sterile gut at birth and achieve this variability by acquiring bacteria early in life. Environmental exposures largely shape the microbiota, including mode of delivery, diet, and medications.
Fecal dysbiosis, defined by an imbalance in the intestinal microbial community, has been demonstrated in patients with CF. Compared to non-CF patients, the fecal microbiome of CF patients typically has decreased microbial diversity, higher abundance of pro-inflammatory microbiota (including Enterobacteriaceae , Staphylococcus , Streptococcus , and Veillonella ), and lower abundance of beneficial microbiota (such as Bifidobacterium ). and Clostridium ). 36,37,38
This imbalance is likely due to perturbations in the CF GI tract that select for altered microbiota, such as ion and fluid abnormalities, abnormal mucus and pH, malabsorption, inflammation, delayed intestinal transit time, and defects in mucosal immune function. 39 Variation in diet (breast milk vs. formula), antibiotic exposure, and gastric acid suppression further shape the fecal microbiome.
Fecal dysbiosis in childhood has been associated with gastrointestinal complications, including early failure of linear growth. Hayden et al. 37 characterized the fecal microbiota of CF during the first year after birth and examined the association between changes in the microbiota and body growth in infants with CF.
By comparing infants with CF and healthy control infants, the authors found that the fecal microbiota of infants with CF showed delayed maturation relative to the fecal microbiota of healthy controls. 37 Furthermore, when comparing short CF infants vs. normal height, found altered abundance of microbes that perform important functions for gastrointestinal health, including decreased Bacteroidetes and greater abundance of Proteobacteria in short infants compared to normal-sized infants. 37
Currently, there are no specific recommendations to prevent or treat dysbiosis in infants with CF. Breast milk has demonstrated positive benefits in patients with CF, including increasing microbial diversity in the fecal microbiota and prolonging the time to initial Pseudomonas aeruginosa colonization and first CF exacerbation, and is the recommended nutritional source for affected infants. 40
Probiotics, although reported to reduce the frequency of CF exacerbations and decrease inflammation and gastrointestinal symptoms, are currently not widely recommended due to a lack of high-quality evidence supporting their use. 41.42
Clinicians should be aware of the potential impact medications may have on microbiome shaping and limit the use of antibiotics and gastric acid suppression unless clinically indicated. This field is evolving rapidly and recommendations may change with new advances in research.
> Rectal prolapse
The incidence of rectal prolapse has decreased since the advent of CN. In early reports, 23% of CF patients experienced rectal prolapse, and 78% experienced prolapse before CF diagnosis. 43 However, in more recent years, the reported incidence is 3.5%, probably due to earlier diagnosis and initiation of pancreatic enzyme replacement therapy (PRT), which is effective in treating most prolapse cases. 44.45}
Manual reduction and treatment of constipation may also be necessary. Surgery or sclerotherapy can be used for complex and refractory cases, although it is rarely necessary, because most cases resolve between 3 and 5 years of age.
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