CF is an inherited autosomal recessive disease with a 2%–4% carrier rate. In 1989, the CF locus was localized through linkage analysis to human chromosome 7q31, and it was discovered that mutations in the CF transmembrane (conductance) regulator (CFTR) gene result in CF. The cell membrane protein coded by CFTR is a 3′–5′-cyclic adenosine monophosphate (cAMP)-induced chloride channel, which also regulates the flow of other ions across the apical surface of epithelial cells. The alteration in CFTR results in an abnormal electrolyte content in the environment external to the apical surface of epithelial membranes. This leads to desiccation and reduced clearance of secretions from tubular structures lined by affected epithelia.

The most common mutation of the CFTR gene, F508del (previously known as ΔF508), is a three base-pair deletion that results in the removal of a phenylalanine residue at amino acid position 508 of the CFTR. Although there are currently 2114 mutations listed in the CFTR database, the F508del mutation is responsible for approximately 70% of abnormal CF genes. ^{, , ,} In families with MI, there is a significantly higher occurrence rate than the expected 25% for an autosomal recessive genetic disorder according to Mendelian genetics. In one series, 79% of CF patients with the F508del mutation presented with abdominal complaints (including MI) rather than pulmonary complaints. However, there is no evidence of distinct allelic frequencies or haplotypic variants in CF patients with MI compared with those without or in CF patients with significant liver disease. ^,

CF is characterized by mucoviscidosis of exocrine secretions throughout the body resulting from abnormal transport of chloride ions across apical membranes of epithelial cells via calcium-activated chloride channels. ^, The role of intracellular calcium concentration on these channels may impact the pathophysiology of CF. Abnormal bicarbonate transport also affects mucin formation in CF. The clinical result is chronic obstruction and infection of the respiratory tract, insufficiency of the exocrine pancreas, and elevated sweat chloride levels. Other clinical variants, such as patients with chronic sinusitis or adult males with congenital bilateral absence of the vas deferens (CBAVD), who typically have little other clinical involvement, have been described ( Fig. 30.2 ). In patients with CBAVD, the CFTR genotype usually includes at least one mild mutation not typical of CF patients. The mild-mutation allele is frequently associated with a severe mutation on the other allele, such as the F508del mutation. ^, The allele G551D is the third most common CF-associated mutation, and patients affected by this mutation may have pancreatic insufficiency, pulmonary symptoms, and an episode of MI equivalent, indicating CBAVD may be associated with a more severe CF phenotype. ^,

Congenital bilateral absence of the vas deferens (CBAVD). (A) Laparoscopic view of a patient’s left internal ring. (B) Compare with a laparoscopic view of a similar-aged patient’s right internal ring with a normal vas deferens.

From Escobar MA, Lau ST, Glick PL. Congenital bilateral absence of the vas deferens. J Pediatr Surg . 2008;43:1222–1223.

Development of both the pancreas and intestinal tract in fetuses with CF is abnormal. In patients with CF, abnormal pancreatic secretions obstruct the ductal system leading to autodigestion of the acinar cells, fatty replacement of pancreatic parenchyma, and fibrosis. Although this process begins in utero, it occurs variably over time. Regardless, pancreatic insufficiency is prevalent in young infants with CF and has a significant impact on growth and nutrition.

Pancreatic insufficiency plays a central role in the pathogenesis of MI. Congenital stenosis of the pancreatic ducts is associated with meconium-induced bowel obstruction. This is further supported by the fact that two-thirds of infants found to have CF by neonatal screening are pancreatic insufficient at birth. However, pancreatic lesions are variable at birth and become more severe in CF children older than 1 year of age. This finding suggests that pancreatic insufficiency is not the leading cause of abnormal meconium in MI. It appears that intestinal glandular abnormalities, specifically an accumulation of acidophilic secretions and dilation of the glandular lumen, contribute more significantly to the production of abnormal meconium ( Fig. 30.3A ). The lack of concordance between MI and the severity of pancreatic disease and the presence of an abundance of intestinal glandular secretions implies that intraluminal intestinal factors contribute more to the development of MI than the absence of pancreatic secretions ( Fig. 30.3B ). ^{, , ,}

Pathological findings consistent with cystic fibrosis are presented. (A) Dilated crypts consistent with cystic fibrosis (between arrows ). (B) Dilated goblet cells consistent with cystic fibrosis ( arrows ).

Abnormal intestinal motility may also contribute to the development of MI. Some patients with CF have prolonged small intestinal transit times. ^, Also, the CFTR ion channel defect results in an exocrine secretion that is rich in sodium and chloride, which can lead to further dehydration of the intraluminal contents, resulting in impaired clearance. Non-CF diseases associated with abnormal gut motility, such as Hirschsprung disease and chronic intestinal pseudo-obstruction, have been associated with MI-like disease, signifying that decreased peristalsis may allow for increased reabsorption of water, thus favoring the development of abnormal meconium. One of the authors (MAE) has cared for two patients with MI and no genetic nor clinical diagnosis of CF; although rare, this has certainly been described.

A recent body of literature describes the prominence of microbial dysbiosis in the development of chronic gastrointestinal symptoms of patients afflicted with CF. It is thought that the loss of the CFTR function results in an initial microbial imbalance in childhood that promotes gut microbiota dysbiosis. The imbalance is compounded in this patient population by increased usage of antibiotics, need for dietary modifications and underlying pancreatic malabsorption resulting in a reduction of overall gut composition microbial diversity and beneficial bacterial species population, and a relative increase in proinflammatory bacteria. ^{, ,} This effect is most profound in the first year of life but persists into adulthood. The functional consequences and clinical implications of such a change are only beginning to be understood, but there is evidence to suggest an association between microbiota dysbiosis and impaired transit time. It is proposed that the gut microbiome may also affect lung health in CF patients through the so-called “gut-lung axis.” ^, The gut-lung axis is an emerging concept defined by the cross-talk between the mucosal environments of the intestine and lung, whereby alterations in the intestinal microbiome have been linked to immunologic and homeostatic changes in the host lungs and vice versa. The specific mechanisms and potential therapeutic implications of this axis are only beginning to be understood.

Since the 1980s, the implementation of newborn screening programs for CF has dramatically increased, particularly in nations with large Caucasian populations. In the United States, the American College of Obstetrics and Gynecology recommends offering CF carrier screening to all women considering pregnancy or women who are currently pregnant. Based on the results of CF screening, the antenatal diagnosis of MI can be made in two different groups: a high-risk group and a low-risk group. In the low-risk group, the diagnosis is suspected when the characteristic sonographic findings of MI are found on routine prenatal ultrasound in a mother with a negative CF carrier screen. Sonographic findings consistent with MI in a fetus with parents who are known carriers of CF and pregnancies after the birth of a CF-affected child are considered high risk. CF was associated with increased relative risk (95% CI [confidence interval]) of 3.5 (2.5–4.9) for low birth weight, 1.6 (1.1–2.4) for small for gestational age, 3.0 (2.2–4.0) for preterm birth, and 6.8 (1.7–26.5) for infant death. Parents of a child with CF are considered to be obligate carriers of a CF mutation.

An algorithm has been established that may be useful in decision making and management of the fetus suspected of having MI on ultrasound (US) (see below; Fig. 30.4 ). If both parents are carriers, evaluation of the fetus should be made by chorionic villus sampling or amniocentesis. In a pregnancy where CF is suspected, sonographic examinations are performed monthly until delivery. This evaluation allows the early detection of potential complications and prepares the clinicians for special or urgent medical or surgical needs upon delivery.

Suggested algorithm for antenatal management of suspected meconium ileus (MI) and cystic fibrosis (CF) and modified the joint Society of Obstetricians and Gynaecologists of Canada (SOGC)– Canadian College of Medical Geneticists (CCMG) Opinion for Reproductive Genetic Carrier Screening. RFLP, Restriction fragment length polymorphism; US, ultrasonography.

Adapted from Irish MS, Ragi JM, Karamanoukian H, et al. Prenatal diagnosis of the fetus with cystic fibrosis and meconium ileus. Pediatr Surg Int . 1997;12:434–436 and Wilson RD, De Bie I, Armour CM, et al. Joint SOGC-CCMG opinion for reproductive genetic carrier screening: An update for all Canadian providers of maternity and reproductive healthcare in the era of direct-to-consumer testing. J Obstet Gynaecol Can . 2016;38(8):742–62e3.

In 2016, the Society of Obstetricians and Gynaecologists of Canada (SOGC)– Canadian College of Medical Geneticists (CCMG) guidelines were updated to recommend offering women and their partners the ability to obtain appropriate genetic carrier screening information and possible diagnosis of genetic disorders, preferably preconception. This would allow for an informed choice regarding genetic carrier screening and reproductive options (e.g., prenatal diagnosis, preimplantation genetic diagnosis, egg or sperm donation, or adoption). The Joint SOGC-CCMG opinion stated that preconception or prenatal education and counseling for reproductive carrier screening requires a discussion about testing within the three perinatal genetic carrier screening/diagnosis time periods (including preconception, prenatal, and neonatal) for conditions currently being screened for and diagnosed. These recommendations applied to screening for cystic fibrosis, and Fig. 30.4 includes these considerations.

Sonographic characteristics associated with MI include a hyperechoic, intraabdominal mass (inspissated meconium; Fig. 30.5 ), dilated bowel, and nonvisualization of the gallbladder. Normal fetal meconium, when visualized in the second and third trimesters, is usually hypoechoic or isoechoic to adjacent abdominal structures. The sensitivity of intraabdominal echogenic masses in the detection of MI/CF is reported to be between 30% and 70%. In addition to MI, hyperechoic bowel has been reported with Down syndrome, intrauterine growth restriction, prematurity, in utero cytomegalovirus infection, intestinal atresia, abruptio placenta, and fetal demise. ^{, , ,} The importance of hyperechoic fetal bowel is related to gestational age at detection, ascites, calcification, volume of amniotic fluid, and the presence of other fetal anomalies. The positive predictive value of hyperechoic masses in a high-risk fetus is estimated to be 52%, but is only 6.4% in the low-risk fetus. It is important to note that hyperechoic bowel has been found to be a normal variant in both the second and third trimesters. ^{, ,}

Ultrasound image of a 22-week gestation demonstrating a 2 × 3 cm intraluminal (distal ileum) mass ( arrows ) consistent with meconium inspissation (meconium ileus).

From Irish MS, Ragi JM, Karamanoukian H, et al. Prenatal diagnosis of the fetus with cystic fibrosis and meconium ileus. Pediatr Surg Int . 1997;12:434–436.

The finding of dilated bowel on prenatal US, in association with a family history of CF, has been reported less frequently than that of hyperechoic bowel. In MI, bowel dilation is caused by obstruction from meconium, but mimics findings in midgut volvulus, congenital bands, intestinal atresia, intestinal duplication, internal hernia, meconium plug syndrome, and Hirschsprung disease. The correlation of dilated fetal bowel and MI suggests that dilated fetal bowel warrants parental testing for CF and continued sonographic surveillance of the fetus.

The inability to visualize the gallbladder on fetal ultrasound has also been associated with CF. Patients with CF have a higher incidence of biliary and hepatic pathology, thought to be secondary to inspissated viscous bile within the biliary system, which may be detected prenatally as nonvisualization of the gallbladder. Combined with other sonographic features, nonvisualization of the gallbladder can be useful in the prenatal detection of the disease. However, caution should be exercised in the interpretation of an absent gallbladder as the differential diagnosis also includes biliary atresia, omphalocele, diaphragmatic hernia, chromosomal abnormalities, and a normal pregnancy.

Fetal magnetic resonance imaging (MRI) is a safe imaging modality increasingly utilized during the prenatal period. MRI identifies meconium distribution in the small bowel, helping to clarify the level of obstruction when compared to US. MRI provides an additional assessment of the colon and rectum with the ability to function essentially as a diagnostic “fetal contrast enema.” Abnormally diminished meconium in the rectum in one report suggested cystic fibrosis or combined small-bowel and colonic obstruction– information that was useful in counseling and preparing for postnatal care.

While recent studies suggest that MRI has the potential to aid in the prenatal diagnosis of meconium ileus, it can also further distinguish and risk stratify patients with simple meconium ileus compared to those with complicated meconium ileus. ^, MRI findings of meconium peritonitis include massive meconium ascites, microcolon and rectum, meconium pseudocyst, peritoneal calcification, dilated bowel loops, and hydrocele with fetal ascites being the most common findings ( Fig. 30.6 ).

Fetal MRI findings of meconium peritonitis in two fetuses receiving surgery. (A–B) A 30-week-old fetus with MP. A transverse 1.5-TT2-weighted image (TR = 15,000 ms, TE = 120 ms) indicates a large amount of ascites and gathering bowel loops (A) and dilated bowels (B). C-D. A 35-week-old fetus with MP. A sagittal 1.5-TT2-weighted image (C, TR = 15,000 ms, TE = 120 ms) reveals a high amount of free ascites in the peritoneal cavity, gathering and distortion of poor filled small intestines, and significant swelling in the left scrotum. A coronal T1-weighted image (D, TR = 234 ms, TE = 4.6 ms) shows distal microcolorectum∗ ( yellow arrow ). ∗Note that while microcolorectum is a term utilized in the radiology literature, the more familiar surgical term is microcolon.

From Lu Y, Ai B, Zhang W, Liu H. Fetal magnetic resonance imaging contributes to the diagnosis and treatment of meconium peritonitis. BMC Med Imaging . 2020;20(1):55.

MI is categorized as either simple or complicated. The thickened meconium begins to form in utero. As it obstructs the midileum, proximal bowel dilatation and thickening, along with congestion, occur. Approximately one-half of these neonates present with simple uncomplicated obstruction. The remaining patients present with complications of MI, including volvulus, gangrene, atresia, and/or perforation, which may result in meconium peritonitis and giant cystic meconium peritonitis. ^,

Simple MI is characterized by a pattern of unevenly dilated loops of bowel on an abdominal radiograph with the variable presence of air–fluid levels ( Fig. 30.10A ). ^{, ,} The absence of air–fluid levels is due to the viscosity of the meconium not allowing an air interface with the fluid. As swallowed air mixes with the tenacious meconium, bubbles of gas may be seen. This soap-bubble or ground-glass appearance depends on the viscosity of the meconium and is not a constant feature. ^{, ,} While each of these features alone is not diagnostic of MI, collectively they strongly suggest the diagnosis, particularly with a family history of CF.

Classic radiographic findings of meconium ileus are seen on these retrograde contrast studies from two different patients. (A) First, the KUB demonstrates diffuse nonspecific dilated loops of bowel. Note there are no air–fluid levels present. (B) Second, a “microcolon of disuse” is seen. The colon is extremely small and unused. (C) Third, inspissated pellets (filling defects) of meconium are seen in the more proximal small bowel in a second patient. Finally, note there is a small bowel obstruction as the contrast material has not reached the markedly dilated loops of small bowel. The first two films were of a neonate with simple MI with no diagnosis of CF.

Radiographic findings in complicated MI vary with the complication. Prenatal ultrasound findings include ascites, intraabdominal cystic masses, dilated bowel, and calcification. Similar findings may be seen on prenatal MRI with fetal ascites being the most common finding. Neonatal radiographic findings may include peritoneal calcifications, free air, and/or air–fluid levels (related to atresia). Air–fluid levels may be minimally present or absent, misleading the clinician to make an incorrect diagnosis of uncomplicated MI. Speckled calcification on abdominal plain films is highly suggestive of intrauterine intestinal perforation and meconium peritonitis. Radiographic findings of obstruction and a large, dense mass with a rim of calcification imply a pseudocyst. These calcium deposits are linear and course along the parietal peritoneum and serosal surface of the visceral organs. Interestingly, one-third of cases of complicated MI have no radiologic findings that suggest a complication.

The diagnosis of CF is established with a sweat test. ^{, ,} A sodium concentration of 60 mmol/L in 100 mg of sweat is diagnostic of CF with 40–60 mmol/L being intermediate (but more likely to be diagnostic in infants) and less than 40 mmol/L being normal. The test is typically performed at several weeks of life to obtain an adequate sample size. The Cystic Fibrosis Foundation recommends:

• Newborns with a positive CF newborn screen should have the test performed bilaterally when the infant weighs more than 2 kg and is at least 36 weeks of corrected gestational age. These measures increase the likelihood of collecting an adequate sweat specimen.

• Newborns greater than 36 weeks’ gestation and more than 2 kg body weight who have a positive CF newborn screen, or a positive prenatal genetic test should have sweat chloride testing performed as soon as possible after 10 days of age– ideally by the end of the neonatal period.

Neonatal CF screening programs using the Guthrie blood spot test for raised concentrations of immunoreactive trypsinogen is available in many countries, but must be confirmed in a two-stage approach incorporating CFTR mutation analysis. ^, Genetic testing for CFTR mutations is available; however, commercial assays test for a limited number of mutations. Most regional laboratories will provide the results for the four or five most common mutations for the relevant ethnic group or geographical region in their area using the amplification refractory mutation system (ARMS) technique. Stool analyses for albumin, trypsin, and chymotrypsin are available, and abnormal values coupled with operative findings suggest CF.

Neonates should initially be managed as any other newborn with intestinal obstruction. This management should include volume resuscitation and ventilator support as necessary. Gastric decompression to prevent progressive abdominal distension, aspiration, and pulmonary compromise is important. In addition, correction of any coagulation disorders and empiric broad-spectrum antibiotic coverage should be initiated.

Newborns with simple MI warrant a trial of nonoperative management. As noted above, the initial management should include an isotonic water-soluble contrast enema (e.g., sodium meglumine diatrizoate or Gastrografin; Bracco Diagnostics Inc., Monroe Township, New Jersey) under fluoroscopic control. The water-soluble enema will also exclude many other causes of neonatal intestinal obstruction. Prior to the water-soluble enema, the neonate should receive adequate intravenous fluid to correct and avoid hypovolemia, receive appropriate electrolyte repletion, and be normothermic. ^,

Under fluoroscopic control, the water-soluble contrast material is slowly infused at low hydrostatic pressure through a catheter inserted into the rectum. Inflation of the catheter balloon should be avoided to minimize the risk of perforation. Upon completion, the catheter is withdrawn, and an abdominal radiograph is obtained to evaluate for perforation. The infant is then returned to the neonatal care unit for intensive monitoring and fluid resuscitation. Successful resolution results in rapid passage of meconium pellets followed by semiliquid meconium, which continues over the ensuing 24–48 hours. Upon instillation of the enema, extraluminal fluid is drawn into the intestinal lumen, hydrating and softening the meconium mass. Warm saline enemas containing 1% N -acetylcysteine (Mucomyst; Apothecon, Princeton, New Jersey) may be given to help complete the evacuation.

Radiographs should be obtained as clinically indicated to confirm evacuation of the obstruction and to exclude late perforation. If evacuation is incomplete, or if the first attempt at contrast enema evacuation does not reflux contrast into dilated bowel, a second enema may be necessary. However, if progressive distension, signs of peritonitis, or clinical deterioration occur, operative exploration is indicated. After two failed attempts at nonoperative water-soluble enemas, operative intervention is likely warranted.

Following successful evacuation and resuscitation, 5 mL of a 10% N -acetylcysteine solution may be administered every 6 hours through a nasogastric tube to liquefy the upper gastrointestinal secretions. Feedings with supplemental pancreatic enzymes for those infants confirmed with CF may be initiated when signs of obstruction have subsided. Pancreatic enzymes and probiotic administration may assist with further clearing of meconium from the gastrointestinal tract. In the past, the success rate of patients with uncomplicated MI, treated with Gastrografin enemas, has ranged between 63% and 83%. ^, However, more recent reports indicate a much lower success rate likely attributable to reluctance to repeat enemas, change in radiologist experience, or the use of isotonic enema fluid. ^,

Several potential complications exist with the use of enemas in treating MI. The risk of rectal perforation can be avoided by careful placement of the catheter under fluoroscopic guidance and by not inflating the balloon-tipped catheter. A 23% perforation rate has been demonstrated in patients when inflated balloon catheters were used, and the risk of perforation increases with repeated enemas. ^, Late perforation, occurring between 12 and 48 hours following the enema, can occur as well. Potential causes of late perforation include severe bowel distension by fluid osmotically drawn into the intestine or by injury to the bowel mucosa by the contrast medium. Lower perforation rates have been reported more recently, possibly related to less aggressive enema attempts and isotonic enema agents. ^, Hypovolemic shock is a risk when delivering hypertonic enemas. Ischemia caused by overdistension is worsened by decreased perfusion, caused by hypovolemia due to inadequate fluid resuscitation.

Postoperative management requires ongoing resuscitation, including maintenance fluids and replacement of insensible and gastrointestinal fluid losses (nasogastric suction and ileostomy). Instillation of 2% or 4% N -acetylcysteine via a nasogastric tube, enterostomy tube, or via an ileostomy or mucous fistula will help solubilize residual meconium. In the patient with fetal or neonatal bowel obstruction, diagnostic tests to evaluate for CF should be performed. Stomas should be closed, when possible, as soon as 4 to 6 weeks, to avoid prolonged problems with fluid, electrolyte, nutritional losses, and cholestatic jaundice. The need for additional operation(s) was noted to be high (22%) in one review of patients with complicated MI, regardless of management type.

Enteral feeding in infants with uncomplicated MI and CF may be initiated with breast milk or infant formula, along with supplemental pancreatic enzymes and vitamins. ^, Caution must be used when prescribing enteric enzyme medication to patients with MI/CF. Treatment failures and complications include fibrosing colonopathy from excessive enzyme doses; and MI equivalent, or distal intestinal obstruction syndrome (DIOS), from inadequate enzyme therapy or generic substitutions for proprietary medications. ^{, ,}

Often patients with a complicated postoperative course will require either continuous enteral feeds or total parenteral nutrition (TPN). Dilation of the small bowel by the obstructing meconium may lead to mucosal damage that could contribute to poor peristalsis or malabsorption. In patients with complicated MI or in those with significant loss of intestinal length, initiating the enteral feeding with a predigested, diluted formula at low continuous volumes is best. If this is well tolerated, the concentration should be increased followed by the volume.

Pancreatic enzymes should be given with enteral feedings (even with predigested formula) starting at 2000–4000 lipase units per 120 mL of full-strength formula. Capsules containing enteric-coated microspheres can be opened and the contents mixed with formula or applesauce in older infants. The microcapsules should not be crushed as this will expose the enzymes to the acid of the stomach where they will be destroyed. Uncrushed pancreatic enzymes should be given, even with MCT-oil containing formulas.

Infants with CF and MI are at increased risk for cholestasis, particularly if they have had, or are receiving, TPN. Alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be monitored weekly. The fluid and nutritional status of infants who have had significant bowel resection (greater than one-third) may be difficult to manage. In addition, the presence of an ileostomy may lead to excessive losses of fluid and sodium. If access to the distal, defunctionalized bowel is possible, drip feeds of glutamine-enriched formula or instillation of the effluent from the proximal stoma (refeeding) may be given at low volumes to enhance bowel growth and help prevent bacterial translocation.

Gastric acid hypersecretion is seen in patients who have short bowel syndrome. An acidic intestinal environment inactivates pancreatic enzymes and prevents dissolution of enteric-coated microcapsules. H ₂ -receptor antagonists or proton pump inhibitors may be used as an adjunct with pancreatic enzyme therapy in patients who have had significant bowel resections. Patients with excessive sweat and intestinal sodium losses may develop a total body sodium deficit. Urine sodium should be measured in infants with ileostomies, especially when there is growth failure, even if serum sodium levels are normal. Those with a urine sodium less than 10 mEq/L will need sodium (and possibly bicarbonate) supplementation. ^,

Although lung disease is usually a later development, mucous plugging and atelectasis can be seen. Pulmonary care with chest physiotherapy should be initiated early in the postoperative period. The head-down position should not be used as this increases the risk of gastroesophageal reflux (GER) and aspiration. Infants should receive nebulized albuterol twice daily followed by chest physiotherapy. Prophylactic antibiotics are contraindicated, and antibiotic therapy should be directed by respiratory cultures, if needed.

The prognosis for CF in the United States has dramatically improved in recent years. CF adults now outnumber CF children in the population with a predicted median survival of 53.1 years in the United States. Similar trends have been noted in CF patients with MI. The prognosis for infants with MI was uniformly poor, despite operative treatment, prior to the mid-1900s. Early series reported mortality rates of 50%–67%. ^, The improved survival in infants with MI can be attributed to many factors. Advances in prenatal diagnosis, pulmonary and neonatal intensive care, nutrition, antibiotics, anesthesia, operative management, and an improved understanding of the pathophysiology and treatment of the CF complications have resulted in dramatic prognostic improvement for infants with both complicated and simple MI. ^, Survival rates of 85%–100% have been reported in uncomplicated MI, and up to 93% in complicated cases. ^{, ,}

Previously, it was thought that patients with CF presenting with MI have worse outcomes than those without MI. From a pulmonary standpoint, however, the data are conflicted. Several long-term follow-up studies of patients with MI report pulmonary function at age 13 years to be no different between those born with and those without MI. ^, One prospective study found children with MI have worse lung function and more obstructive lung disease than those with CF but without MI. This was also the finding in a recent retrospective case-control study from Australia that followed patients out to a median age of 15 years and found worse pulmonary function and lower BMI among those with MI, which they associated with more hospitalization, nutritional interventions, and mortality. ^, What has become more clear, however, is the nutritional impact of MI on prognosis. Comparison of the nutritional status of a similar population of patients with CF suggests that those who presented with MI suffer long-term nutritional complications and other problems including lower bone mineral density. ^,

GERD occurs with increased prevalence in patients with CF. Aspiration in CF children may aggravate failure to thrive, adversely affect pulmonary function, and may account for the predilection of CF lung disease in the right upper lobe. ^, Pathological reflux with endoscopic and histological esophagitis is present in more than 50% of CF patients and the incidence of GERD in patients with CF is approximately 80% in patients younger than 5 years. A recent large multicenter, prospective study found that in the majority of CF patients, typical GERD symptoms are absent. Therefore, diagnostic procedures should be considered in at-risk patients. ^, It is clear that early diagnosis and treatment of GERD is important if complications are to be minimized and respiratory function maximized.

Antireflux medications, modification of chest physiotherapy, and eliminating the 30 degrees head-down tilt may all decrease the incidence of GERD in this population. Children unresponsive to medical management should undergo evaluation for an antireflux procedure that includes pH-multichannel intraluminal impedance. ^, Our preferred approach is the laparoscopic Nissen fundoplication. Data suggests that a fundoplication may improve respiratory function (improved FEV1 slope) in CF children with mild versus moderate disease. ^, Patients with symptomatic GERD requiring an antireflux procedure may benefit from concurrent placement of a gastrostomy if they have inadequate caloric intake.

Barrett esophagus, a rare finding in children, has been reported in older children with CF. ^, Although an antireflux procedure may halt the advancement of metaplasia, if dysplasia is present, the malignant potential remains. In cases with metaplasia, endoscopic monitoring is the same for patients with CF as for those without. In adults, if high-grade dysplasia is confirmed by two pathologists and aggressive medical therapy fails to eliminate the dysplasia, esophagectomy was traditionally recommended. This paradigm has shifted recently, with most dysplasia treated with a combined endoscopic approach of mucosal resection and radiofrequency ablation. With so little data available in children with CF, those with dysplastic esophageal changes were often considered candidates for an antireflux procedure. However, a panel of pediatric and adult gastroenterologists recently reviewed best practices in the management of the gastrointestinal aspects of CF. They found fundoplication exacerbated esophageal dysmotility and could be a risk factor for Barrett’s esophagus and esophageal cancer. Thus, the management of esophageal dysplasia is still evolving in CF. Finally, at least one case of metastatic esophageal adenocarcinoma has been reported in a 40-year-old patient with CF.

Given the high expression of CFTR gene throughout the biliary tree, patients with CF are predisposed to biliary tract disease. It is proposed that the loss of CFTR results in a disrupted alkaline balance and pH dysregulation, dehydration of bile, and an increased vulnerability to bacterial endotoxins, resulting in an increased sensitivity to inflammation. Within the pancreas, multiple macroscopic cysts may replace the pancreatic parenchyma in CF. Although it has been thought that hepatic and pancreatic dysfunction occurred together, hepatic dysfunction may occur in patients with normal pancreatic function. Cystic fibrosis liver disease (CFLD) encompasses a wide spectrum of hepatic complications including steatosis, cholangiectasis, fibrosis, focal biliary cirrhosis, multilobular biliary cirrhosis, neonatal cholestasis, atretic gallbladder, cholelithiasis, sclerosing cholangitis, and biliary dyskinesia. ^, Obstruction of intrahepatic biliary ductules by abnormal mucoid secretions or inspissated bile, resulting from the absence of functional CFTR in bile duct epithelial cells, results in the development of cirrhosis in patients with CF. When biopsied, the classic liver histology in CF is focal biliary fibrosis with progression to multilobular, biliary cirrhosis. Prolonged cholestatic liver disease in CF patients may lead to cirrhosis, portal hypertension, and ultimately liver failure and death without liver transplantation.

Though more common in older patients with CF, intrahepatic cholestasis can be seen in the neonate. In extreme forms, this process can be associated with a marked decrease in ductal diameter, varying from hypoplasia to atresia. Additionally, these neonates are at increased risk for cholestatic jaundice when they are not being fed enterally. Cholestatic jaundice is suggested by prolonged jaundice unresponsive to choleretics, nondilated bile ducts and gallbladder on ultrasound, absent biliary excretion on nuclear scan, and characteristic liver biopsy findings. Interestingly, unsuspected cirrhosis was seen in 3.3% of young patients with CF who were prospectively evaluated in a multicenter study. Although ursodeoxycholic acid has been used in the treatment of cystic fibrosis-associated liver disease, a recent Cochrane review found insufficient evidence to justify its routine use in cystic fibrosis. Currently, there is insufficient data to guide the use of ursodeoxycholic acid for the management of children with CF cirrhosis.

Progressive CFLD should be recognized early, and prompt referral made to a hepatologist for further evaluation and treatment. The following findings are concerning for progressive CLFD: palpable hepatomegaly or splenomegaly, declining platelet count, and increased echogenicity, nodularity, or heterogeneity on hepatic ultrasound. End-stage liver disease (ESLD) is manifest by loss of synthetic function, growth failure, or portal hypertension presenting as variceal hemorrhage. Although abnormal liver function tests have been noted in 13% of CF patients, only 4.2% manifest overt liver disease (although the prevalence is as high as 37%, depending on the definition of liver disease). In one study of severe liver disease in CF, splenomegaly was observed in 99% of patients and varices in 71%. Levels of liver enzymes were near normal in most patients. Thrombocytopenia affected 70% of patients and was more severe in patients with varices. Severe liver disease developed early in childhood (approximately 10 years of age) and was more common in boys than girls.

The management of complications from CF cirrhosis in children differs from that of the adult population. Beta-adrenergic blockers are frequently used in the adult population to reduce the risk of variceal hemorrhage. However, their effects are not well studied in children and they are typically avoided in CF patients due to the increased risk of bronchoconstriction. Similarly, prophylactic endoscopic band ligation is frequently utilized in the adult population but remains controversial in children given the lack of data. Portosystemic shunts, transjugular intrahepatic portosystemic shunts (TIPS), partial splenectomy, and endoscopic injection sclerotherapy have been advocated in treating CF patients with portal hypertension. Other surgical options for these patients are direct ligation of the varices, esophageal transection, or the Sugiura procedure (gastric devascularization). ^, These procedures are all palliative, with orthotopic liver transplantation (OLT) being the only curative treatment for portal hypertension and end-stage liver disease.

Progressive CFLD with decompensated CF cirrhosis should prompt evaluation for liver transplantation. Indications for liver transplantation in CF do not differ from those children in liver failure without CF. Survival after OLT may be worse compared to non-CF patients, given the multiorgan involvement. However, the outcomes are good, with 5-year survival rates for children and adults of 85.8% and 72.7%, respectively. ^, There are several successful reports of combined liver and intestinal transplantation, combined liver and pancreas transplant, kidney transplant after combined heart and lung transplants, and triple organ transplant (pancreas, liver, and kidney) in patients with exocrine pancreatic insufficiency and insulin-dependent diabetes related to CF. ^, Long-term studies have shown preservation or maintenance of respiratory function and nutritional status following OLT in patients with CF. ^, Interestingly, diabetes is common pretransplantation and posttransplantation in CF solid organ transplant recipients, but pancreas transplantation remains rare, even though combined or pancreas-only transplant outcomes remain favorable (2-year posttransplantation survival was 88% after liver-pancreas transplant, 33% after lung-pancreas transplant, and 100% after pancreas-kidney and pancreas-only transplants).

Gallbladder disease is prevalent in the CF population, including cholelithiasis in up to 24%. ^{, ,} Other abnormalities include microgallbladder, absent gallbladder or atretic cystic duct, and hyperviscous mucus. Unsurprisingly, adult patients with CF are also at increased risk of both gallbladder and biliary tract malignancy. Many CF patients with gallstones are asymptomatic, with the incidence of symptomatic gallbladder disease in CF reported to be approximately 4%. Bile in patients with CF is not cholesterol supersaturated and the stones are composed of protein and calcium bilirubinate, making the stones radiolucent. ^{, ,}

CF patients with symptomatic gallbladder disease should undergo prompt laparoscopic cholecystectomy. ^, Due to the low incidence of common bile duct (CBD) stones in CF patients, routine intraoperative cholangiograms or preoperative endoscopic retrograde cholangiopancreatography (ERCP) are not needed. ^, It was previously thought that the biliary tract abnormalities often encountered in patients with CF make penetration of radiocontrast dye into the biliary tract during ERCP difficult. However, it is now recommended that ERCP with potential balloon dilation or stenting should be considered for CF patients presenting with either symptomatic biliary strictures or choledocholithiasis. Intraoperative cholangiography may be necessary if jaundice, pancreatitis, cholangitis, dilated CBD, or palpable stones in the CBD are present.

Distal intestinal obstruction syndrome (DIOS) (formerly called MI equivalent) is a recurrent, partial or complete intestinal obstruction unique to teenage and young adult patients with CF that occurs secondary to abnormally viscid mucofeculent material in the distal ileum and right colon ( Fig. 30.14 ). DIOS has been defined as an acute complete or incomplete fecal obstruction in the ileocecum, whereas constipation is a gradual fecal impaction of the total colon. The etiology of DIOS is unclear, but these patients are more likely to have a history of steatorrhea from pancreatic exocrine insufficiency despite adequate enzyme therapy.

This 17-year-old with cystic fibrosis and history of cecostomy tube placement presented with crampy abdominal pain that was localized to the right lower abdomen. In addition, he also had a decreased frequency of defecation. (A) Axial CT revealed the ground-glass appearance in the loops of bowel on the right side are typical findings in a patient with distal intestinal obstruction syndrome. (B) Coronal CT revealed dilated loops and abnormally viscid mucofeculent material in the distal ileum. This patient responded well to oral polyethylene glycol with relief of his symptoms.

Several aspects particular to gastrointestinal function in the CF patient may help to explain this syndrome. In addition to inherently slow intestinal motility, other contributing factors may include thickening of chyme secondary to the presence of undigested protein and fat, precipitation of undigested protein and bile acids in duodenal fluid with reduced pH, lower water content of pancreatic and duodenal secretions, hyperviscosity of mucus resulting from abnormal ion and water transport, abnormal regulation of mucin secretion, and altered biochemical properties of mucus glycoprotein. Precipitating factors include sudden withdrawal of (or noncompliance with) enzyme supplementation, immobilization, dehydration, respiratory tract infections, and recovery from surgery.

DIOS occurs in 15%–37% of patients with CF with estimates of prevalence ranging from 5 to 12 episodes per 1000 patients per year in children and higher rates reported in adults. DIOS is particularly associated with exocrine pancreatic insufficiency with malabsorption and severe pulmonary limitation. ^{, , ,} It occurs with increasing frequency following organ transplantation, with one study citing 44% of cases having had a prior lung transplant. Another report noted a 12% incidence in children with CF, with most (63%) having a history of MI as an infant. ^{, ,} Patients with an initial episode of DIOS could be as much as 10 times more likely to incur a second episode, which has led to the claim “DIOS begets DIOS.” ^,

Another study reviewed long-term follow-up of CF patients with DIOS. Among patients with DIOS, the distribution of DIOS episodes over a >20-year period was as follows: 23.1% study patients had only one episode of DIOS in their lifetime, 26.9% had two episodes, 26.9% had three episodes, and 23.1% had four or more episodes. Compared to the control group, DIOS patients had a significantly higher incidence of Aspergillus spp . colonization and a higher number of hospitalizations due to respiratory exacerbations. Other associations include liver disease, diabetes mellitus, and Pseudomonas aeruginosa . Considering these associations, some have proposed a potential link between the altered gut microbiota in CF patients and the development of DIOS. ^, Female gender was associated with recurrent DIOS, constipation with incomplete episodes, and poor patient compliance in taking pancreatic enzyme therapy during complete episodes. Children with normal fat absorption are rarely affected.

Patients with DIOS present with crampy abdominal pain, often localized to the right lower quadrant, and decreased frequency of defecation. They may complain of insidious, debilitating abdominal pain. Physical examination in uncomplicated DIOS usually reveals abdominal distension and a tender mass (palpable fecal matter) in the right lower quadrant with no evidence of peritonitis. Typically, there is no fecal impaction on rectal examination and the stool is guaiac negative. Different degrees of obstruction can occur, ranging from partial (most common) to complete with vomiting, abdominal distension, and obstipation.

A supine and erect abdominal film is the most useful initial investigation when DIOS is suspected ( Fig. 30.15 ). This will show distended small bowel with scattered air– fluid levels and a granular, bubbly pattern of intestinal gas representing the mixing of air and inspissated fecal matter in the right lower quadrant, similar to infants with MI. Inspissated material in the right colon and distal ileum can be demonstrated with a water-soluble contrast enema. With this study, an ileocolic intussusception, which can also be seen in CF patients, can be excluded, and the contrast study itself may prove therapeutic in some cases.

This 18-year-old with cystic fibrosis presented with crampy abdominal pain that was localized to the right lower abdomen. In addition, he also had a decreased frequency of defecation. (A) The ground-glass appearance in the loops of bowel on the right side is a typical finding in a patient with distal intestinal obstruction syndrome. (B) The upright abdominal film shows air–fluid levels. This patient responded well to a contrast enema with relief of his symptoms.

The diagnosis of DIOS should take into consideration other potential causes of abdominal pain and intestinal obstruction in CF patients. This constellation of signs and symptoms has historically been a diagnostic dilemma in these patients. Intussusception, mechanical small bowel obstruction due to adhesions, appendicitis, Crohn disease, and biliary tract disease may present similarly.

In the absence of mechanical small bowel obstruction due to adhesions, intussusception, or appendiceal disease, a trial of medical management aimed at relieving the inspissated distal bowel obstruction is suggested. Therapeutic Gastrografin (Bracco Diagnostics Inc., Monroe Township, New Jersey) enema has been particularly efficacious and should be considered as first-line therapy for DIOS patients. Alternatively, after adequate volume resuscitation and colonic enema washout, a balanced polyethylene glycol-electrolyte solution, such as GoLytely or Colyte, can be given orally or by nasogastric tube. The dose is 20–40 mL/kg/h with a maximum of 1200 mL/h. Early aggressive laxative treatment with oral laxatives (polyethylene glycol) or intestinal lavage with balanced osmotic electrolyte solution and rehydration is successful in greater than 90% of cases. ^{, , ,} Younger patients will usually require nasogastric tube placement whereas older children may be able to ingest sufficient volumes of lavage solution. Constipation can generally be well controlled with polyethylene glycol maintenance treatment. Given the increased risk for future episodes of DIOS, long-term management should include dietary modification, lifestyle adjustment, and a step-up bowel regimen with gradual therapeutic escalation titrated to patient symptoms.

The passage of stool, resolution of symptoms, and the disappearance of a previously palpable right iliac fossa mass imply successful treatment. Sequential abdominal radiographs will help to document the resolution of DIOS, but if symptoms persist then the differential diagnosis must be reconsidered. Some authors have recommended DIOS prophylaxis with use of scheduled laxatives and high dietary fiber.

When there is complete obstruction or evidence of peritonitis, an operation is necessary and oral or rectal therapies are contraindicated. Previous laparotomy (odds ratio [OR] 28.5, 95% CI 1.3–624, P = .03) and a history of meconium ileus (OR 14, 95% CI 1–192, P < .05) were statistically significant predictors of progression to surgical management. Early surgical referral is important in these children. ^, A nasogastric tube should be passed for decompression and adequate resuscitative measures initiated. At laparotomy, the bowel wall will feel thickened and filled with tenacious material. It can be decompressed and irrigated via a small catheter placed through the appendiceal stump, as previously described for uncomplicated MI. It is also possible to leave a tube in situ to irrigate the bowel postoperatively. Some children may require lysis of adhesions and/or bowel resections, with either primary anastomosis or, rarely, creation of an ostomy.