Gastrointestinal Manifestations of Cystic Fibrosis

Radiologic-Pathologic Correlation

Abstract Introduction Intestinal Obstruction and Its Complications Nonobstructive Bowel Manifestations

Pancreatic Abnormalities Hepatobiliary Abnormalities CF and Gastrointestinal Malignancy

Prognosis and Future Perspectives Summary Source Information References

Intestinal Obstruction and Its Complications

Meconium Ileus

Meconium ileus is the earliest clinical manifestation of CF, occurring in 10%-15% of patients (20,21). Virtually all infants with meconium ileus prove to have cystic fibrosis (22). Meconium ileus is not associated with a specific CF genotype. Abnormal meconium in babies with CF most likely results from primary dysfunction of secretory intestinal epithelium (23,24). Mechanical obstruction occurs when desiccated meconium pellets occlude the distal small bowel, whereas the more proximal small bowel loops are distended with tenacious green to black meconium paste (Figure 1, Figure 2, Figure 3). An unused microcolon develops when antenatal obstruction isolates the large bowel from the normal passage of meconium.

Clinically, newborn infants present with abdominal distention, bilious emesis, and failure to pass meconium within 48 hours. A history of polyhydramnios may be obtained. Two types of meconium ileus are recognized: simple and complicated. Simple meconium ileus typically presents within 48 hours of birth as intestinal obstruction in an otherwise healthy infant (19). Meconium ileus is complicated by volvulus in 50% of cases (25). These infants present earlier and with more severe symptoms. Prolonged volvulus produces ischemia, necrosis, perforation, and peritoneal spillage of meconium, which incites an inflammatory response. The liberated meconium is contained as a pseudocyst or disseminated as generalized meconium peritonitis. Once perforated, the bowel may seal over before birth. With or without associated volvulus, one or more areas of bowel atresia may develop antenatally when intestinal ischemia is followed by segmental bowel resorption (Figure 4) (26).

Spilled meconium may also enter the scrotum through the processus vaginalis testis, which communicates freely with the intraabdominal peritoneal space during testicular descent. Meconium hydrocele has also been described in the newborn scrotum. A case of meconium hydrocele producing a labial mass in a newborn was recently reported; the rarity of this phenomenon was attributed to early obliteration of the processus vaginalis in the female fetus compared with the male fetus, which decreases the likelihood of meconium passage from the abdomen (27).

Antenatal ultrasound (US) may reveal nonspecific dilatation of the fetal bowel (24). After birth, abdominal radiography demonstrates distal intestinal obstruction. The absence of sharply defined air-fluid levels on gravity-dependent projections (Figure 5) has been attributed to abnormally thick intraluminal meconium (28). Inspissated meconium mixed with air in the terminal ileum produces a speckled pattern in the right lower quadrant, classically described as a soap bubble appearance (Figure 5) (29). If the antenatal course was complicated by perforation and meconium peritonitis, radiographs may demonstrate separation of bowel loops by fluid, peripherally calcified pseudocysts (Figure 6), scattered punctate calcifications throughout the abdomen, or scrotal calcifications. Contrast material enema examination reveals an unused microcolon and multiple filling defects in the distal ileum and colon, findings that represent inspissated meconium pellets (Figure 5, Figure 7) (30).

The water-soluble contrast material enema procedure has been used successfully for both the diagnosis and treatment of meconium ileus, but the choice of agent is controversial. The efficacy of diatrizoate sodium solution with polysorbate 80 (Gastrografin with Tween 80; Squibb [now Bracco Diagnostics], New Brunswick, NJ) was originally attributed to its high osmolality, then to the wetting agent Tween, which Gastrografin no longer contains (31). Hypertonic water-soluble contrast agents produce fluid shifts and dehydration by drawing water into the bowel lumen and may cause mucosal irritation (32). Deaths from necrotizing enterocolitis have been reported following the use of Gastrografin or Renografin-76 (Bracco Diagnostics) to treat meconium ileus (33,34). Newer nonionic contrast agents in less hyperosmolar formulations are safer but more expensive. Dilute solutions of conventional ionic contrast agents (17% Hypaque [Nycomed, New York, NY] or Conray [Mallinckrodt, St Louis, Mo] mixed with N-acetylcysteine) have been advocated as a compromise (32). They are less expensive than Gastrografin and contain no flavoring agents that may contact the peritoneum if perforation occurs (31). In one series, one-third of neonates with meconium ileus were treated successfully in this way and required no further intervention (35). The low-osmolar nonionic media may be reserved for clinically fragile infants and for those considered to be at high risk for bowel perforation.

Although plain radiographs demonstrate dilated bowel loops containing a soap bubble pattern in 50%-66% of CF patients with meconium ileus, this finding is nonspecific (32). Identical findings may be seen in Hirschsprung disease, small bowel atresia without meconium ileus, meconium plug syndrome unrelated to CF, small left colon syndrome, imperforate anus, and obstruction due to a duplication cyst. Abdominal or scrotal calcifications are strong evidence of prior perforation and meconium peritonitis, but the most common cause of meconium peritonitis is small bowel atresia without CF (25).

Meconium Plug Syndrome

Meconium ileus is the most common cause of distal intestinal obstruction in an infant with CF. However, abnormal meconium uncommonly produces colonic, rather than distal ileal obstruction. Twenty-five percent of infants with meconium plug syndrome prove to have CF (36). In these cases, the contrast material enema study shows a normal colon caliber with an obstructing filling defect representing a meconium plug. The plug may be mobilized during the enema, providing immediate relief of the obstruction. Meconium plug syndrome may also be the presenting sign in Hirschsprung disease and has been associated with prematurity and maternal treatment with magnesium sulfate (37,38).

The terms meconium plug syndrome and small left colon syndrome are often used interchangeably, creating confusion. The term small left colon syndrome refers to a transient functional obstruction due to immaturity of the myenteric plexus, most commonly seen in infants of diabetic mothers (39,40) but also attributed to maternal substance abuse (41). In this condition, the colon caliber becomes abruptly diminutive distal to the splenic flexure, in association with bowel dilatation proximal to this transition site. A meconium plug is occasionally associated with small left colon syndrome, in which case it represents the result, rather than the cause, of the obstruction. Thus, obstruction persists even after relief of the meconium plug during a contrast material enema procedure, and the functional immaturity of the distal colon gradually resolves over days to weeks. Typically, small left colon syndrome is unrelated to CF. In one case report, however, radiologic features consistent with small left colon syndrome were found in an infant with CF (42).

Distal Intestinal Obstruction Syndrome

In the older child or young adult with CF, the distal small bowel may by obstructed by thick stool. This condition was called "meconium ileus equivalent" by Jensen in 1962 (43). Because meconium is not present beyond early infancy, the term distal intestinal obstruction syndrome is now recommended (19). Pathologic mechanisms for this syndrome include inspissated intestinal secretions and pancreatic insufficiency, undigested food residue, disordered intestinal motility, fecal stasis, and dehydration (19).

Distal intestinal obstruction syndrome occurs in 10%-15% of patients with CF (44). Clinically, the term has come to encompass abdominal pain from fecal impaction or constipation, palpable cecal masses that may pass spontaneously, and complete obstruction of the terminal ileum or right colon by puttylike fecal material (19,44). Patients typically present with recurrent bouts of colicky abdominal pain associated with a palpable fecal mass (45). Abdominal distention and flatulence are common, and a normal stooling pattern may be present despite the intestinal obstruction. The clinical findings may mimic those of appendicitis or partial intestinal obstruction due to stricture or adhesions from previous bowel surgery. However, despite the common distention of the appendix by inspissated secretions, the reported prevalence of acute appendicitis in CF patients is lower than that in the general population (46).

Radiographs of the abdomen demonstrate dilated small bowel loops and a bubbly ileocecal soft-tissue mass (25). Contrast material enema examinations not only help define the fecal mass but may also relieve the obstruction. Indeed, the water-soluble contrast material enema procedure has become an accepted supplement to other nonsurgical therapeutic measures, including regular oral doses of pancreatic enzymes, stool softeners, and oral polyethylene glycol-electrolyte solutions (Go-lytely, Braintree Laboratories, Braintree, Mass). Multiple enemas with iso-osmolar contrast agents over several days may be required to mobilize the tenacious stool plugs. Computed tomography (CT) has been reported to be an effective tool in monitoring the progress of medical therapy in distal intestinal obstruction syndrome (47).

Intussusception

Intussusception complicates CF in approximately 1% of patients, and CF is an important cause of intussusception beyond infancy (48). Unlike patients with idiopathic intussusception, of whom 75% present before 2 years of age (49), children with CF typically present with intussusception after 4 years of age, with an average age of almost 10 years (48). Most intussusceptions are ileocolic, resulting from adherent fecal residue and enlarged lymphoid follicles in the terminal ileum. A chronically distended appendix may also be the lead point. Intussusception may occur in the setting of distal intestinal obstruction syndrome; the sticky fecal mass serves as a lead point, facilitated by a chronically dilated and hypotonic colon.

In children with CF and intussusception, symptoms of intermittent, severe, crampy abdominal pain may be milder and the passage of bloody stool less common than in patients with idiopathic intussusception (48). This difference in clinical presentation may be caused by a relatively large hypotonic colon with chronic fecal distention (19). Older patients learn to recognize the signs of intussusception and may become facile at manual reduction of their intussusception.

The radiologic features of intussusception due to CF (Figure 8) are identical to those seen in the general population, which have been well described (49,50,51,52). Briefly, screening abdominal radiographs may demonstrate a soft-tissue mass with an abnormal intestinal gas pattern in 50%-60% of patients. An additional 25% of patients with intussusception have findings consistent with small bowel obstruction. When intussusception is suspected clinically, radiographs are considered normal only when there is unequivocal demonstration of the air-filled cecum. Sonography reveals a doughnut sign on transverse scans, composed of a central area of increased echogenicity (the intussusceptum) surrounded by hypoechoic edematous bowel (the intussuscipiens), and a pseudokidney appearance on longitudinal images. Similarly, CT shows a target configuration composed of edematous bowel and mesenteric fat displayed in cross section. An air or positive contrast material enema study demonstrates an obstructing lobulated soft-tissue mass, which may exhibit a coiled spring appearance of approximated mucosal folds. The intussusceptum may be reduced under fluoroscopic guidance by performing a hydrostatic or pneumatic enema; the relative merits and disadvantages of each technique continue to be the subject of debate in the radiology literature (53,54).

Fibrosing Colonopathy

Colonic stricture is a recently recognized cause of distal intestinal obstruction in patients with CF (55,56,57,58,59,60,61,62,63,64,65). Between January 1990 and December 1994, 35 histologically confirmed cases of colonic stricture were reported to the U.S. Cystic Fibrosis Foundation (66). The cause has not been definitely established, but high-strength pancreatic enzyme supplementation compounded by a high protease intake has been strongly implicated (67).

In one study of 10 children (mean age, 5.5 years) with CF and colonic stricture, all the children had been switched from standard strength to high-strength pancreatic enzyme replacement 6-49 months before diagnosis of stricture (55). The right colon was involved in all but one patient, who had undergone right hemicolectomy in infancy. Seven patients underwent surgical resection of the involved segment of colon, which had irregular mural thickening with variable, severe luminal narrowing. Histologic findings included severe submucosal fibrosis and fatty infiltration, sometimes with transmural involvement. No granulomas, crypt abscesses, vasculitis, or fistula formation were present to suggest Crohn disease.

Radiologic findings included mucosal irregularity and spiculation, with nodular thickening of the colonic wall; loss of normal haustral markings; shortening of the colon; and long-segment luminal narrowing, which ranged from mild stricture to complete occlusion (Figure 9). Transverse and descending colon strictures worsened in one patient following ileostomy, suggesting that further exposure to pancreatic enzyme replacement is not necessary for disease progression.

The term fibrosing colonopathy has been applied to both the prestricture state and the progression to true strictures in association with high-dose pancreatic supplements (66). Colonic shortening, focal or extensive narrowing, and poor distensibility seen at contrast material enema studies are considered highly suggestive of the prestricture state. Multiple endoscopic biopsies are currently recommended for patients with positive findings from contrast material enema studies, and the biopsy results support the diagnosis of fibrosing colonopathy when fibrosis of the lamina propria is identified (66).

Abstract Introduction Intestinal Obstruction and Its Complications Nonobstructive Bowel Manifestations

Pancreatic Abnormalities Hepatobiliary Abnormalities CF and Gastrointestinal Malignancy

Prognosis and Future Perspectives Summary Source Information References