Meconium Ileus

Meconium ileus is the intestinal obstructive variant of cystic fibrosis or mucoviscidosis. Approximately 15% to 20% of infants with cystic fibrosis also present with intestinal obstruction related to meconium ileus. Although it was originally thought that cystic fibrosis primarily affected the pancreas, and that abnormal pancreatic secretions resulted in abnormal meconium that became obstructive, this is now known not to be the case.

Cystic fibrosis

Cystic fibrosis is the most common life-shortening inherited disease in North America. If there is a family history of cystic fibrosis, the chance of the condition recurring in a family is approximately 1 in 4. The disease was first described clinically by Dr. Dorthy Andersen in 1938 and is a complex disorder of both the respiratory and digestive systems. The genetics of cystic fibrosis well understood to be inherited by an autosomal recessive pattern, with families with the disease carrying a 1 in 4 chance of having another child with the disorder. The incidence of heterozygous carriers in whites is approximately 1 in 20. People with European extraction have a 1 in 3,200 incidence of having a child with cystic fibrosis, whereas the incidence decreases to 1 in 15,000 in African-Americans, and much less in Asians. The genetic mutations responsible for the disorder were first identified by Dr. Francis Colins in 1989. Since this first genetic mutation was isolated, over 800 mutations have been identified. The loss of a single pheylalanine at position 508 of the gene (靈508) represents up to 70 to 80% of mutations in patients with cystic fibrosis, and 50% of those in North America.

The gene, CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP regulated chloride channel, and is located on the long arm of chromosome 7q and spans 250 kb. Functionally the gene encodes a protein which is responsible for regulating the opening and closing of chloride channels. This protein is is the most important apical membrane transporter for chloride. The defect affects all epithelial lined structures. Although the precise manner in which the deficient chloride transport leads to the numerous manifestations of the disease has not been completely resolved, it appears that the CFTR gene may also influence sodium transport, and may lead to an overly activated sodium pump. Cystic fibrosis actually is associated with an abnormality of exocrine gland secretion throughout the body. Thus there is abnormally viscid mucous secretion in the lungs, pancreas, intestine, biliary tree, and elsewhere. This is also why approximately 90% of patients with cystic fibrosis have failure of secretion of pancreatic enzymes into the duodenum, which results in malabsorption of fat and other nutritional substances. Major nutritional abnormalities may result in such cases.

In the intestine, this leads to the migration of water out of the intestinal lumen with inspisation of meconium and subsequent formation of an obstructive state. Diagnosis of cystic fibrosis should be pursued in all children who present to surgeons with the following surgical disorders: meconiuim ileus, meconium plug syndrome, rectal prolapse, jejunal ileal atresias, nasal polyps, neonatal jaundice, portal hypertension failure to thrive and pancreatitis.

Diagnosis of cystic fibrosis may be performed using a variety of tests. Because it is not possible to test for all of the hundreds of genetic mutations, a number of approaches are utilized. Newborns may be tested with a dried blood spot for immunoreactive trypsinogen (IRT). This has a high sensitivity, but a high false positive rate, which demands that additional testing be performed. Sweat chloride testing (positive if >60meq/L) is quite accurate, and most patients should undergo this test. Only 1.4 % of CF patients will have a normal test (4% in Israel), but the test depends on the ability to collect sufficient quantities of sweat (at least 100mg obtained after maximal stimulation by pilocarpine iontophoresis) which may be difficult in neonates. Genetic testing is increasing utilized. Commercial testings typically examine DNA for 25 to 100 of the most common mutations (95% of all CF patients). Genetic diagnosis for the identification of heterozygotes or for detecting cystic fibrosis in utero has been described, but the ethical issues which this raises have not been sufficiently dealt with in North America.

Pathophysiology of meconium ileus

Because the small intestinal mucous glands produce overly thick secretions even in utero, the meconium formed by these infants is abnormally viscid, sticky, and adherent. Characteristically in meconium ileus, the proximal ileum is greatly dilated and contains thick, sticky meconium, while the distal ileum and colon are collapsed and obstructed by thickly packed round mucous plugs that resemble rabbit pellets (Figure 69-2A). Infants born with this form of the disease have so-called simple meconium ileus or simple obturation obstruction of the intestine. However, in utero this may progress to complicated meconium ileus. In such a process, the massively dilated proximal intestine volvulizes (see Fig. 1. If this occurs early in gestation, one or more atresias may be produced. If volvulus of the redundant ileum occurs late in gestation, infants may then present with perforation with either free or encysted meconium peritonitis. Each of these presentations has different clinical, radiologic, and therapeutic considerations. In a rare instance the proximal and distal portions of the volulized limbs may reanastomose and manifest themselves as a child with ileal stenosis.

Diagnosis

Intestinal obstruction in infants with meconium ileus is generally evident within 24 to 48 hours following birth. Although a family history of cystic fibrosis is certainly helpful, it is only present in only a few percent of patients (no more than 1 in 4). In approximately 20% of patients, particularly those with complicated meconium ileus, there is a history of maternal polyhydramnios. Although meconium ileus is uncommon in premature infants, many are dysmature or small-for-dates. Associated congenital malformations are uncommon.

With meconium ileus, three cardinal signs of intestinal obstruction are generally evident including generalized abdominal distention, bilious vomiting, and failure to pass meconium within 48 hours. At times it is possible to feel a dilated intestinal loop filled with obstructing meconium. With complicated meconium ileus, patients generally present either at or shortly following birth because of severe abdominal distention that is often associated with respiratory distress. At times the abdominal wall is red and inflamed. Progressive hypovolemia may lead to cardiovascular instability, and such infants appear extremely ill. Plain radiographs of the abdomen may be extremely helpful. In patients with simple obturation obstruction, the characteristic radiologic features include varying-sized loops of distended intestine, a relative absence of air-fluid levels, and a "soap bubble" appearance of portions of the abdomen (Neuhauser's sign), particularly the right lower quadrant (Figure 2A). Other disorders that may share some of these radiologic findings include Hirschsprung's disease, ileal atresia, and meconium plug syndrome.

Complicated meconium ileus is suggested on plain film of the abdomen when areas of calcification are seen or when there is a large dense mass with a rim of calcification evident, suggestive of cystic meconium peritonitis. The development of intraperitoneal calcifications may occur within 4 days following a perforation of the intestine. Liberated lipases and bile salts cause an intense chemical peritonitis which leads to the deposition of calcium in the peritoneal cavity and within the wall of the intestine. Such a process may leave the child with a massive peudocyst formation with diffuse meconium peritonitis. When simple meconium ileus is suspected, a contrast enema study should be performed. The classic finding is a microcolon along with pellet-like meconium when contrast is refluxed into the terminal ileum (Figure 2B). In general, this begins with the use a nearly iso-osmolar water soluble contrast material (e.g., Cystoconray II), and should the appearance be suggestive of meconium ileus, this material is evacuated and replaced with a water soluble contrast material of higher osmolarity since efforts may then be used to wash out the obstructing plugs and inspissated meconium (see treatment below). In patients with complicated meconium ileus, a contrast enema study is used primarily to confirm the diagnosis and to determine the position of the colon. However, in patients with complicated meconium ileus, a contrast enema study is not necessarily required before laparotomy as the plain films are often sufficient in these instances to indicate the diagnosis. Following relief of intestinal obstruction, the diagnosis of cystic fibrosis should be verified.

Treatment

Simple Meconium Ileus

Noblett described a method for washing out obstructing plugs in patients with meconium ileus of an uncomplicated nature. With this method, soluble contrast material such as meglumine diatriazoate (Gastrografin) is used. Regardless of the contrast material used, it must be water soluble to help loosen the inspisated pellets of meconium. Additionally, water soluble agents are much safer in case a perforation occurs during the study. Where the use of a hyperosmolar to draw fluid into the intestinal lumen is necessary has not been well documented. Gastrografin has a strikingly high osmolarity (2150 mOsm), this may result in serious fluid derraingments in patients, and typically agents such as Hypaque (1450 mOsm) or cystoconray II (404 mOsm) are being increasingly used. The following criteria must be met before attempting contrast enema management of uncomplicated meconium ileus. The preliminary diagnostic study should have excluded other causes of distal intestinal obstruction, and there should not be any clinical or radiologic signs of complicated meconium ileus. The patient must be prepared beforehand in terms of correction of fluid and electrolyte abnormalities. Patients should be bolused with 10 ml/kg of isotonic saline, and maintained at 1.5 times maintenance fluid rates for at least 8 to 12 hours following the study. Broad spectrum antibiotics should be administered; and the patient must be evaluated ahead of time by the responsible pediatric surgeon. Additionally, the contrast enema should never be performed without fluoroscopic control. Undue pressure must not be used, but the procedure may be repeated two or three times provided that the patient does not show any signs of physiologic deterioration. Otherwise, surgery should be undertaken. Continuing attention to fluid and electrolyte and acid-base balance is mandatory in patients who are being managed in this fashion. Approximately 30% of patients with simple meconium ileus may be managed this way, but the percent success varies widely in reported series. The remainder will require operative management.

In simple meconium ileus, the goal of surgery is to completely evacuate the obstructing plugs and meconium from the ileum proximal and distal to the point of obstruction.

One method that may be used is to irrigate the intestine and colon clear of plugs of obstructing meconium via an enterotomy in the dilated segment of ileum. At times intestinal resection and primary anastomosis may be needed provided that all of the plugs can be washed out of the distal intestine and colon. An alternative method in patients in whom the distal bowel cannot be cleaned out, or whose condition is precarious, is the formation of an ostomy, with a secondary closure once respiratory and nutritional factors are stabilized. Historically, a Bishop-Koop procedure had been advocated. This consists of a Roux-en-Y anastomosis between the end of the dilated proximal segment and the side of the collapsed distal segment approximately 4 cm from the distal open end, which is brought out as an ileostomy (Fig 3). This is generally utilized much less frequently in recent years. Most surgeons now approach patients with the formation of a double barrel stomas. The ostomy provides an opportunity for catheter placement and irrigation of distal obstructing plugs. Although somewhat cumbersome, one can introduce a tube into the distal stoma andintroduce gastrointestinal effluent from the proximal stoma. The Santulli procedure (opposite configuration to a Bishop-Koop) is another approach to the formation of a decompressing stoma which has also been primarily discarded. In this technique a Roux-en-Y anastomosis between the end of the collapsed distal ileum and the side of the dilated proximal segment with exteriorization of the proximal segment. All of the exteriorization procedures may require early closure of the ostomy because of excessive fluid loss, except for the Bishop-Koop procedure, which at times closes on its own.

Complicated Meconium Ileus

By definition, complicated meconium ileus indicates that the infant has intestinal atresia or perforation with varying degrees of meconium peritonitis. Under these circumstances, the findings at operation dictate what should be done. Adhesions are lysed, and inflammatory membranes decorticated sufficiently to permit identification of enough of the intestine to manage the pathology. Such patients require careful preoperative and intraoperative management to replace fluid and blood loss. Necrotic and atretic intestine should be resected, and then it is generally best to perform exteriorization using a double-barreled enterostomies. In rare instances, the adhesions are so dense that anatomy cannot be discerned enough to perform a stoma. In such cases, peritoneal drainage tubes can be placed to allow passage of meconium, until the inflammatory process subsides after a couple of months.

Postoperatively, careful attention must be given to fluid and electrolyte as well as acid-base balance initially, and management of pulmonary complications, such as atelectasis and infection. These patients also require careful nutritional management, balancing intravenous and enteral nutrition. Because of pancreatic insufficiency, supplemental pancreatic enzymes and administration of lipid-soluble vitamins are required. Because of varying degrees of protein, fat, and carbohydrate malabsorption, special formulas such as Pregestamil that contain hydrolized casein and MCT oil are generally best. Finally, patients with small bowel stomas may loose large amounts of zinc, magnesium, bicarbonate and sodium. Monitoring and replacement of these deficiencies is essential. Spot urine sodiums should be performed, as the finding of a urine sodium less than 10 mEq indicates total body sodium depletion. Failure to thrive will occur unless such patients must receive sodium supplementation.

Complications

In addition to periodic atelectasis and pulmonary infection, many patients have gastrointestinal complications including malabsorption, biliary obstruction from inspissated bile, and adhesive intestinal obstruction.

In older children a meconium ileus-like picture that has been termed meconium ileus equivalent may occur that affects approximately 10% of cystic fibrosis patients. The clinical picture is identical to that of simple meconium ileus in newborns and meglumine diatriazoate enemas are usually sufficient for relief. Additional pancreatic enzyme supplementation is then provided. Such patients also benefit from polyethylene glycol-based oral agents. In the mid-1990's the use of high concentrations of pancreatic enzymes (mean dose 19,000 units per kilogram per day) resulted in the development of colonic structuring in a number of cystic fibrosis patients. These children required resection of the deformed colons. Although this process appears to have not reappeared with alternative enzyme agents, the pediatric surgeon should have a high index of suspicion for this process in patients on high dose pancreatic enzyme regimens.

Results and Outlook

In recent years survival has improved with current operative mortality being 10% to 20%. The long-term outlook is the same as for all patients with cystic fibrosis where the average life expectancy is now in the range of 32 years (based on 1998 statistics). Lung transplantation has recently become a promising option for selected patients with end-stage pulmonary disease related to cystic fibrosis.

For Physicians

Meconium plug and the neonatal small left colon syndromes (Figure 4)

Although meconium plug and neonatal small left colon syndromes are considered clinically distinct entities, they share sufficient similarities to be considered together. The basic pathophysiology is that of transient neonatal colonic obstruction, and the principles of diagnosis and management are similar. The important distinction in the recognition of these syndromes is that they are associated with colonic obstruction as differentiated from the picture seen with meconium ileus, where the small bowel is involved. Although emphasis has previously been placed on the theory that meconium plug and small left colon syndromes result from obturation obstruction of the colon by abnormal meconium, it is more likely that these disorders result from transient motility disorders of the distal colon related to immaturity.

Diagnosis

These infants present with significant degrees of abdominal distention, bile-stained vomitus, and failure to pass any stool during the first day or two of life. In over 50% of patients with small left colon syndrome, there will be a maternal history of diabetes. Plain films of the abdomen demonstrate massive intestinal distention with air-fluid levels. Contrast enemas characteristically demonstrate a dilated colon proximal to a tapered transition zone at varying levels with meconium plug syndrome, and characteristically at the splenic flexure in neonatal small left colon syndrome. The radiographic picture on contrast enema study is suggestive of Hirschsprung's disease, but characteristically such patients typically improve following the contrast enema, particularly if meglumine diatriazoate or other water soluble contrast is used. Occaisionally, the enema may need to be repeated.

Treatment

Ordinarily, soluble contrast enemas relieve patients with meconium plug syndrome or neonatal small left colon syndrome. Surgery is rarely required except in unusual instances where perforation may have occurred. In infants of diabetic mothers, appropriate perinatal management of hypoglycemia may be necessary. Since the clinical and radiologic picture is similar to that of Hirschsprung's disease, suction biopsy of the rectum should be performed in these patients to rule out Hirschsprung's disease. Provided that the infant does not have Hirschsprung's disease, there are no long-term complications. Cystic fibrosis may initially present itself with a meconium plug. Work-up for cystic fibrosis should be performed in infants with this condition.

Figure Legend

Figure 1. A. Simple obturation obstruction by inspissated meconium pellets. B. Complicated meconium ileus in three forms: atresia, volvulus, and perforation.
Figure 2. Radiographs of infant with meconium ileus. A. Plain flat plate of abdomen. Note soap-bubble appearance in right lower quadrant (arrows), and poorly defined air/fluid pattern. B. Contrast enema with microcolon and inspisated meconium in the terminal ileum (arrows).
Figure 3. Operative options for the surgical treatment of meconium ileus.
Figure 4 A. Barium enema study shows the classic findings of meconium plug syndrome. Note that even though the distal colon was collapsed on film, once the plug was evacuated, bowel movements were normal, and suction rectal biopsy demonstrated ganglion cells to be present. B. Barium enema study in a newborn (whose mother was diabetic) who failed to stool within 48 hours of birth demonstrates the typical findings of neonatal small left colon syndrome. This is not Hirschsprung's disease but most likely a temporary motility disorder that will resolve in a few days.

Suggested Readings

Berdon, WE, Slovis, TL, Campbell, JB: Neonatal small left colon syndrome: its relationship to aganglionosis and meconium plug syndrome. Radiology 125(2):457-462, 1977. Emphasizes the occasional association of small left colon syndrome and Hirschsprung's disease.

This information is provided by the University of Michigan Department of Surgery, Section of Pediatric Surgery and is not intended to replace the medical advice of your doctor or health care provider. Please consult your health care provider for advice about a specific medical condition. For additional health information, please contact your health care provider or our offices.