Cystic fibrosis (CF) is an autosomal recessive disease that causes chronic morbidity and decreases the life-span of most affected individuals. Because of a defect at a single gene locus that encodes a protein, the cystic fibrosis transmembrane regulator (CFTR), individuals with cystic fibrosis have defective cyclic adenosine monophosphate-regulated chloride transport in epithelial cells of exocrine organs. Although the exact pathophysiology remains to be clarified for each involved organ, there is an accumulation of viscous secretions associated with progressive obstruction and subsequent destruction of excretory ducts.

Chronic pulmonary disease is the major cause of morbidity in the majority of patients. These individuals have progressive bronchiectasis and associated bacterial endobronchial infections, most often secondary to Pseudomonas species.

Although the pulmonary disease is most prominent, the GI manifestations of cystic fibrosis are extensive and contribute to significant morbidity and even mortality. This section will review the clinical problems related to the gastrointestinal tract, particularly the pancreatic insufficiency and hepatic disease in cystic fibrosis.

Approximately 80% of patients with cystic fibrosis are born with pancreatic insufficiency, and another 5-10% develop pancreatic insufficiency in subsequent years. These patients have marked impairment of pancreatic exocrine function, including decreased secretion of water, bicarbonate, lipase, amylase and proteinases from the pancreas into the duodenum. In the very young, the endocrine function of the pancreas is usually normal, but many gradually develop evidence of glucose intolerance; a small number develop clinical diabetes requiring insulin therapy. Patients with pancreatic insufficiency may present with any of the following clinical entities with or without pulmonary disease.

Meconium ileus is partial or complete obstruction of the intestine, commonly the ileum, with thick inspissated meconium. This occurs in approximately 15% of infants with cystic fibrosis. Any infant with meconium ileus must have cystic fibrosis excluded. These infants may present with delayed passage of meconium, abdominal distention, vomiting or other signs of obstruction. Meconium ileus may be complicated by antenatal or postnatal volvulus, atresia, perforation of the bowel and meconium peritonitis. In cases with complications, infants may require surgery shortly after birth. Extensive bowel resection may leave them with the short bowel syndrome.

These infants are investigated initially with a plain abdominal x-ray for evidence of obstruction or perforation. If the bowel perforates in utero the perforation often seals, and the x-ray may show calcifications from the meconium in the peritoneum. If meconium ileus is a possibility, surgery should be considered immediately. As long as the x-ray shows no evidence of free air (implying a perforation), most infants are given a gentle water-soluble contrast enema to attempt to relieve the obstruction or at least outline the obstruction for the surgeon. These enemas can cause significant fluid shifts in small neonates, so an IV must be running during the procedure. If the procedure is unsuccessful, surgery is required. The majority of infants with meconium ileus also have pancreatic insufficiency, but this condition can occur in pancreatic-sufficient patients as well.

After the neonatal period, chronic diarrhea with or without failure to thrive is common. These infants have loose stools essentially from birth, and one may obtain a history of delay in the passage of meconium. The parents may describe the diarrheal stools as being pale, foul smelling, fatty and/or soupy. The diarrhea is primarily secondary to fat malabsorption because of the pancreatic insufficiency. However, infants who have had small bowel resection, such as for bowel atresia secondary to meconium ileus, may have mucosal disease secondary to bacterial overgrowth. This will contribute significantly to the diarrhea and may cause it to become more watery. Initially, if they do not have respiratory problems, infants with cystic fibrosis tend to have a relatively good appetite and can in some cases compensate for the extreme loss of nutrients by increasing their intake. As they develop pulmonary symptoms or become gradually malnourished, however, their appetite will decrease.

In cystic fibrosis, failure to thrive is usually a result of a combination of decreased intake, loss of fat in the stools and increased metabolic requirements. The requirements of the average cystic fibrosis patient have been reported to be 120% of normal. Nevertheless, some patients have essentially normal caloric requirements, and others may have requirements in excess of 150% of normal. Many in the early childhood years are able to maintain their nutritional status well with pancreatic enzyme supplementation and good nutrition. Unfortunately, the increased caloric requirements of puberty coupled with deteriorating lung function often make it impossible for the most severely affected patients to maintain their nutrition and normal growth. In addition, CF patients may have anorexia of chronic disease and difficulty eating due to chronic cough. They present with a gradual decrease in growth percentiles, first of the weight and subsequently of the height. Puberty may be delayed or arrested in the early stages. At this time, nutritional supplementation becomes extremely important. Pancreatic enzyme supplementation must be maximized, and nutritional supplementation given either orally or by enteral tube feeding. Total parenteral nutrition is rarely required. If enteral feeds are needed, we use nasogastric tubes in all our patients except those who have nasal polyps. These patients are taught to put their nasogastric tubes down five to six nights a week to obtain 10 hours of nocturnal supplementary feedings. We have had patients as young as 4 years of age who are able to put their own tubes down. The optimal supplement to use is still being debated. We have been most successful with regular high-calorie formula such as Ensure^® with fiber, particularly in patients who have evidence of glucose intolerance. Some centers do not give pancreatic enzyme supplements with the tube feeding; others give enteric-coated enzymes at the initiation of tube feeds; still others add pancreatic enzyme powder to the feeds. We have had the most success with the last approach. With infants, we use the enteral tube feeds in those who present with significant failure to thrive and are unable to take enough calories for catch-up growth, and also in those who have had small bowel resections. Generally, these infants will require the tube feeding only for several weeks to months. We have had only two children between the ages of 2 and 9 who have needed enteral tube feeding. In the adolescent group who require enteral feeding supplementation, we find that about 50% require the supplementation for only a transient period of six months to two years while they are experiencing the significant growth of puberty. A small number of our patients have had to remain on the enteral tube feeding program for years in order to maintain their weight and nutritional status.

As a result of significant malabsorption prior to treatment, patients may present with overt evidence of bruising or bleeding due to vitamin K deficiency. We have seen one infant female who presented with this condition as well as evidence of xerophthalmia, apparently due to vitamin A deficiency. The clinical effects of vitamin E deficiencies in cystic fibrosis are not well documented, but this vitamin must be given to patients in a supplement and in adequate doses. We also supplement with vitamin D, although vitamin D deficiency, particularly evidence of rickets, is very uncommon in patients with cystic fibrosis.

In spite of their pancreatic insufficiency, most patients with cystic fibrosis do not have difficulty with hypoalbuminemia secondary to protein malabsorption. Protein malabsorption, however, is a problem in infants who are fed a soy protein formula, and sometimes in those who are breastfed. These infants will present with significant hypoalbuminemia, edema and usually a history of diarrhea. We have had at least one infant who presented with heart failure secondary to severe hypoalbuminemia. Feeding with soy formula must be discontinued, but often those who are receiving breast milk may have their albumin corrected with pancreatic enzyme supplementation. Older patients with severe malnutrition or cor pulmonale may also develop hypoalbuminemia.

An infant with untreated pancreatic insufficiency becomes increasingly malnourished and continues to pass numerous stools, and thus may begin to have regular rectal prolapse. This is not infrequently the complaint that brings the infant to medical attention. In these cases, a diagnosis of cystic fibrosis must be made quickly and the child renourished. The prolapse will resolve with appropriate nutrition and pancreatic enzyme supplementation to decrease the stooling. In most of these infants the rectal prolapse reduces spontaneously. If it does not, it must be gently reduced manually.

The distal intestinal obstruction syndrome (DIOS), also known as meconium ileus equivalent, is partial or complete obstruction of the bowel resulting from fecal masses, usually in the cecum. This can occur in any age of child with cystic fibrosis, but we find it most often in the older child. Younger children with DIOS present with decreased appetite, decreased stooling, distention and often vomiting. Older patients complain of grumbling or crampy abdominal pain and a gradual decrease in stooling. In most patients, the fecal masses are easily palpated and an x-ray is not always required. If the diagnosis is made early, most can be treated with N-acetylcysteine given orally. We give a loading dose in a cola drink and 3 subsequent doses (1 dose every 6 hours over 24 hours). Fluids must be encouraged during this time. If there is evidence of marked obstruction, we admit the patients to hospital and give them polyethylene glycol-salt solution (GoLYTELY^TM) orally or by nasogastric tube. This completely clears the obstructive fecal masses. It is essential to ensure that patients with DIOS get adequate enzymes, as the syndrome seems to occur most often in patients who are not getting enough enzymes or in whom the duodenal pH is too low for optimal efficacy of the enzymes.

Five to 10% of patients with cystic fibrosis will remain pancreatic-sufficient throughout their life. Unfortunately, some pancreatic-sufficient patients develop pancreatitis, which may present with vomiting and acute pain that radiates to the back or with recurrent low-grade abdominal pain and perhaps a change in appetite. Those who present with acute pancreatitis should be treated as any other patient with pancreatitis. The bowel is rested until the enzymes return essentially to normal and the patient is asymptomatic. In patients who are found to have mild abdominal pain and only slight increase in enzymes, management is less definitive. We have treated these patients with pancreatic enzymes to try to decrease the amount of stimulation of the pancreas. Unfortunately, the pancreatitis tends to be a recurrent problem in some individuals.

Hepatobiliary disease in cystic fibrosis is well documented. Fortunately, although a significant number of patients have subtle manifestation of hepatobiliary abnormalities, only a small number have severe liver disease. Given the increasing life expectancy of patients with cystic fibrosis there may be an increasing need to manage patients with severe liver problems. The following briefly outlines the clinical features of some of the hepatobiliary problems associated with cystic fibrosis.

Prolonged conjugated hyperbilirubinemia is reported to occur in neonates with cystic fibrosis. In some cases, the hyperbilirubinemia may be secondary to a problem unrelated to the cystic fibrosis; nevertheless, any infant with conjugated hyperbilirubinemia of unknown origin should be investigated for cystic fibrosis.

A significant portion of patients with cystic fibrosis have mildly elevated liver enzymes, including alkaline phosphatase, g-glutamyl transferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). This is not uncommon in patients who had a meconium ileus as a neonate and are pancreatic-insufficient. In most of these patients, the enzymes either normalize or remain slightly elevated throughout their life. A small proportion develop serious liver disease.

Many patients with cystic fibrosis have a slightly large liver secondary to fatty infiltration, probably because of poor nutrition. In these patients, the liver is smooth and soft. In those who develop progressive liver disease, the liver is initially large; it gradually begins to feel hard and often nodular. Splenomegaly is usually not detected until the patient is aged 6 or older. On histologic examination, these patients have multinodular or biliary cirrhosis. The liver disease tends to progress slowly and the prominent clinical problems are secondary to hypersplenism. It can be years before there are changes in the albumin, INR/PT or PTT, or an elevation of the bilirubin. With the significant portal hypertension, the patients are at risk for bleeding from esophageal or small bowel varices. As the life-span of patients with cystic fibrosis increases, one would expect to see increasing morbidity and mortality from liver failure.

In very recent years, ursodeoxycholic acid has been used to try to improve the liver disease in cystic fibrosis. Short-term studies report that patients treated with ursodeoxycholic acid show improvement in their liver enzymes and, in some cases, in liver function studies. It has yet to be determined whether long-term treatment will actually prevent progression of the liver disease and perhaps protect some children from developing cirrhosis.

As there are numerous gastrointestinal problems in cystic fibrosis and their interrelationship can be quite complex, it is beyond the scope of this section to discuss the management in detail. In the majority of cases, the problem must be identified, assessed and managed as in patients without cystic fibrosis. Nevertheless, because the pancreatic insufficiency causes most of the gastrointestinal problems, an approach to its management will be outlined.

There are several indirect methods that assess pancreatic insufficiency, but the only direct measurement of pancreatic function is a pancreatic stimulation test. Unfortunately, this test requires intubation of the duodenum, it is invasive and uncomfortable for the patient, and generally it will not contribute significantly to the patient's management. Therefore, this test is usually reserved for complicated cases. We usually assess the pancreatic insufficiency by a 72- hour fecal fat collection, which measures the percentage of fat lost in the stools daily. If possible, this test is done before the patient is placed on pancreatic enzyme supplementation and post-enzyme supplementation.

Once the pancreatic insufficiency is diagnosed, it is treated with supplementary pancreatic enzymes. The aim of treatment is to control the fat malabsorption so that the patient has normal growth and good nutrition. (In the majority of cases it is impossible to reduce fecal fat loss to less than 12%, even on optimal enzyme supplementation.) Commonly, the enzymes given are in capsule form and contain enteric-coated spheres of lipase, amylase and proteinases. These enteric-coated spheres are released in the alkaline environment of the duodenum. The strength of these preparations varies; usually the dosage is expressed in lipase units. We find that the appropriate dosage of lipase is best determined empirically.

We begin giving infants under 6 months of age at diagnosis 1 enteric- coated capsule with 4,000 units of lipase per feed. By 1 year of age, the majority will be on 8,000 to 10,000 lipase units per feed and 4,000 per small snack. Subsequently, the enzymes are evaluated and increased as the patient grows and whenever there is evidence of increasing malabsorption. By age 8 the majority of patients with pancreatic insufficiency will require 80,000 to 100,000 lipase units per meal. In most cases an increase in lipase above this level does not improve their fat absorption. In older children, we generally use capsules containing 20,000 lipase units each, so that the child can take fewer capsules per meal. The disadvantage with this is that the child may be taking more enzymes than required for small meals or snacks.

With the lack of bicarbonate secretion from the pancreas, the duodenal pH may be too low for optimal activity of the pancreatic enzyme supplements. In patients in whom the number of enzymes seems maximal for age and weight, ranitidine is started at 2 mg/kg b.i.d. to enhance the efficacy of the enzymes.

The gastrointestinal effects of cystic fibrosis are extensive. Most of the prominent problems are secondary to the pancreatic disease. Once this is treated adequately with enzymes, vitamin replacement and adequate nutrition, many problems will resolve. Severe liver disease is less common; it can be devastating in the patients in whom it occurs and may be of more concern as the life- span of the patients increases. Research into the pathophysiology of the liver disease and into pharmacologic agents such as ursodeoxycholic acid is ongoing. Because failure to thrive and liver disease can present insidiously, it is essential to monitor these patients on a regular basis, including documentation of height and weight, a complete physical examination and a regular biochemical evaluation.