Given the high frequency of cystic fibrosis in the white population, most pediatricians are likely to encounter affected individuals in the course of their practice. The familiar pulmonary manifestations usually dominate the clinical picture of children with cystic fibrosis. However, because 85% of affected children have exocrine pancreatic insufficiency, the large majority will display at least some gastrointestinal symptoms (Table 1). Furthermore, in the child with stable mild to moderate lung disease, it is not unusual for gastrointestinal conditions to present the major morbidity, which at times may even be life threatening. This is not surprising given the widespread tissue distribution of the abnormal cystic fibrosis transmembrane conductance regulator gene product in a variety of epithelia. As the life expectancy of individuals with cystic fibrosis continues to increase due to improved pulmonary and nutritional care, hepatobiUary complications are likely to become more clinically apparent. This article reviews some of the more common gastrointestinal manifestations of cystic fibrosis and outlines an approach to the evaluation of the cystic fibrosis patient with persistent diarrhea or liver function test abnormalities.
Approximately 80% to 85% of patients with cystic fibrosis have pancreatic insufficiency, characterized by a decrease in the secretory capacity of both digestive enzymes and bicarbonate to a degree causing clinical malabsorption. In general, enzyme secretion must fall below 2% of normal values before such clinical symptoms manifest.2 Of the 15% to 20% of individuals without clinical pancreatic insufficiency, approximately one half will have decreased enzyme secretion by careful quantitative testing.3 Some of these will be impaired sufficiently so that they will ultimately develop pancreatic insufficiency over time as ongoing pancreatic injury accumulates. The other half of pancreatic-sufficient individuals will have normal enzyme secretion, although they still have the chloride and fluid secretion defect that results in concentrated pancreatic secretions. Pancreatic insufficiency can be correlated with cystic fibrosis genotype in that it is virtually always associated with specific "severe" genotypes, such as the most common ΔF508, and is uncommon in other milder phenotypes.4
Gastrointestinal Manifestations of Cystic Fibrosis*
The symptoms of pancreatic insufficiency in infancy include frequent, loose, oily, malodorous stools. In the toilet-trained child, these bulky, floating stools may be described as difficult to flush; however, in the infant using diapers, they may not be recognized as abnormal. Failure to thrive is common and is often the presenting symptom leading to the diagnosis of cystic fibrosis. Parents may describe their infants or young children as having ravenous appetites.
The diagnosis of pancreatic insufficiency in cystic fibrosis is made clinically based on the finding of increased fecal fat excretion. Although fat stains performed on random stool samples may qualitatively suggest steatorrhea, 7 2 -hour stool collection on a defined diet is desirable to quantify the degree of fecal fat loss. Whereas normal infants absorb more than 93% of ingested dietary fat, untreated infants and children with cystic fibrosis on average will absorb only 62%, although there is wide variability.3
Treatment of pancreatic insufficiency consists of oral pancreatic enzyme supplementation with feedings. These enzymes are available in powdered or tablet forms, and as enteric-coated microtablets contained in capsules. Powdered forms often are used in infancy because of the young infant's difficulty in handling the enteric-coated products and the concern of oral bums if the microtablets are not completely cleared from the mouth. As infants begin to accept textured-food feedings, enteric-coated enzymes are used to enhance the delivery of active enzyme to the small bowel at greatly reduced doses.
Enzyme dosage is empiric based on control of steatorrhea and adequate weight gain, but starting doses can be estimated at 2000 to 4000 units of Upase per 120 mL of infant formula or breast-feeding in early infancy, and 1000 units per kilogram of body weight per meal for older infants and children up to approximately 4 years of age.5 As children grow older, their per kilogram enzyme doses typically decrease to the order of 500 units per kilogram per meal. In the past, liberal upward adjustment of enzyme doses have often been made empirically because of the apparent clinical safety of these products. However, it recently has become clear that indiscriminantly high enxyme doses are associated with the risk of developing fibrosing colonopathy. As a result, the apparent requirement for enzyme dosages markedly exceeding the above guidelines generally indicates a secondary contributing problem requiring further investigation6 (Table 2).
Pancreatic-sufficient patients will not require enzyme supplementation initially. However, a subset of children who are initially pancreatic sufficient will ultimately cross the threshold to pancreatic insufficiency; consequently, they should be monitored longitudinally for clinical signs of malabsorption.
Endocrine Pancreatic Insufficiency
Endocrine pancreatic insufficiency in cystic fibrosis can be documented by abnormal glucose tolerance testing in 20% to as many as 42% of individuals.7 Overt insulin-dependent diabetes is relatively less common, occurring in approximately 8% of affected individuals and generally presenting after the first decade of life.8 Diabetic ketoacidosis is uncommon, and glucose control is usually easily managed.
Pancreatitis may occur in patients with cystic fibrosis and pancreatic sufficiency,9 although it has rarely been reported in those with pancreatic insufficiency as well. Presumably, by the time an individual has the requisite near-total destruction of the gland to render them pancreatic insufficient, they have too little residual enzyme production to produce pancreatic inflammation. In the pancreatic-sufficient cystic fibrosis patient with recurrent episodes of abdominal pain, the diagnosis of pancreatitis must be entertained. Conversely, in any undiagnosed child with recurrent episodes of acute pancreatitis, one must exclude cystic fibrosis as the underlying cause.
The earliest intestinal manifestation of cystic fibrosis is meconium ileus, which may occur in 10% to 15% of affected infants and is virtually pathognomonic of the diagnosis of cystic fibrosis. Meconium ileus generally presents in the first day or two of life with symptoms of bowel obstruction, including abdominal distension and vomiting. An abdominal radiograph typically will demonstrate dilated bowel loops with a gasless, "ground-glass" appearance in the right lower quadrant, representing inspissated meconium in the distal ileum. Meconium ileus most commonly occurs in pancreatic- insufficient patients but has been documented in pancreatic-sufficient patients as well.10 Approximately 50% of patients with meconium ileus will be uncomplicated and can be treated medically. Treatment consists of lavage or enema administration of a hyperosmolar nonionic contrast agent, such as diatrizoate, to draw fluid into the bowel lumen and displace the meconium obstruction. The main risk of this therapy is the danger of significant fluid and electrolyte shifts, necessitating close monitoring and intravenous fluid support as needed. Uncommonly, cases of meconium ileus without perforation may be refractory to such treatment and lead to laparotomy for relief of the obstruction. The surgeon typically will attempt intraoperative bowel irrigation, but if unsuccessful, a limited resection may be required.
Pancreatic Enzyme Therapy in Cystic Fibrosis*
The remaining 50% of cases of meconium ileus will be complicated by perforation, volvulus, or intestinal atresia. When perforation occurs in utero, it may be apparent after birth in the form of intraabdominal calcifications or meconium peritonitis. In such complicated cases, bowel irrigation is obviously contraindicated, and treatment must be surgical.
Rectal prolapse first occurs most commonly after 1 year of age and usually prior to the implementation of pancreatic enzyme therapy. As a result, in those with mild lung disease, rectal prolapse may be the present - ing symptom of cystic fibrosis. When it occurs in established patients already on enzyme replacement, it is commonly associated with inadequate control of steatorrhea. The passage of frequent stools and poor nutritional status resulting from ongoing steatorrhea both appear to contribute to the causation of the prolapse. However, because it also occurs (albeit less frequently) in those who are pancreatic sufficient, other factors, such as chronic cough and viscous intestinal secretions, also must be considered to play a role. Although the majority of otherwise healthy children with isolated rectal prolapse will not have cystic fibrosis, some would argue that all such children should be screened with sweat chloride testing. At the very least, one ought to maintain a low threshold for sweat testing of any child with rectal prolapse and any other clue, including marginal growth, a history of pneumonia, asthma or sinusitis, recurring rectal prolapse, or a family history of cystic fibrosis.
Just as rectal prolapse is commonly associated with untreated or inadequately treated steatorrhea, correction of the steatorrhea usually will result in resolution of the symptom. In the cystic fibrosis patient who has already been on enzyme therapy, the development of rectal prolapse should prompt an investigation for the presence and cause of persistent steatorrhea (Table 2). In addition, aggressive nutritional support is warranted and may contribute to improved pelvic floor muscle support. Even if these measures are unsuccessful in completely eliminating episodes of rectal prolapse, the patient and his or her family generally become quite adept at reducing the prolapse at home and can manage this nuisance with the reassurance that it is likely to spontaneously resolve by the early elementary school years.11 A rare patient may require a surgical approach to this problem due to frequent and symptomatic rectal prolapse.
The older child with cystic fibrosis is at risk for the development of constipation. The primary fluid secretory defect in cystic fibrosis is invoked as contributing to this problem. Furthermore, the energy-dense, high-fat diet necessary to maintain good growth and contribute to good pulmonary function tends to be lower in fiber. Constipation should be treated as in any other child, including encouraging fiber intake to the degree possible, although this is practically limited by concerns over energy intake and finicky palates. Laxative agents, such as mineral oil or milk of magnesia, may be required in these cases.
Distal Intestinal Obstruction Syndrome
A relatively common cause of abdominal symptoms in the older child with cystic fibrosis is distal intestinal obstruction syndrome, formerly referred to as meconium ileus equivalent. Distal intestinal obstruction syndrome presents with colicky abdominal pain, abdominal distension, and vomiting suggestive of bowel obstruction. The symptoms are due to obstruction of the distal small bowel with inspissated stool and mucus, which may be palpable as a mass on examination of the right lower quadrant. The differential diagnosis must include intussusception, because this also may occur in cystic fibrosis patients with inspissated stool.12 Traditionally, therapy has consisted of N-acetylcysteine by mouth or lavage. More recently, good success in relieving the obstruction has been achieved with the use of polyethylene glycol-balanced electrolyte solutions.13 Symptoms are often recurrent and when they are, the implementation of a prophylactic regimen of regular lavage may be indicated.
A relatively recently recognized complication of the treatment of cystic fibrosis is fibrosing colonopathy. This condition is characterized by the development of fibrotic strictures in the colon or more rarely by diffuse fibrotic constriction of longer segments of the colon. This entity first gained attention in 1 994 after the introduction of high-dose pancreatic enzyme preparations containing lipase doses in excess of 20000 units per capsule.14 These high-dose products reduced the number of capsules required to achieve large enzyme doses and patients with persistent steatorrhea could be treated with dramatically increased enzyme doses. As cases of fibrosing colonopathy began to appear in greater numbers, the temporal association with excessive enzyme dosing emerged, and the high-dose products have subsequently been withdrawn from the market. It should be emphasized that it is not the high-dose capsules per se that have been correlated with the risk of developing fibrosing colonopathy, but rather the total enzyme dose even if delivered by lower dose capsules. Presumably, tissue injury results from high local concentrations of digestive enzymes in the bowel lumen.
Additional risk factors for the development of fibrosing colonopathy include age younger than 12 years, a history of meconium ileus or distal intestinal obstruction syndrome, prior intestinal surgery, or a diagnosis of inflammatory bowel disease. Based on epidemiologie data, fibrosing colonopathy is associated with doses in excess of 6000 lipase units per kilogram per meal for periods longer than 6 months.6 It appears to be rare at lower doses, and this forms the basis for current recommendations not to exceed doses of 2500 lipase units per kilogram.
The diagnosis of fibrosing colonopathy should be suspected in any patient with the above risk factors who develops persistent diarrhea, abdominal pain, or evidence of obstruction. Contrast enema examination will reveal colonie shortening and narrowing, with lack of normal bowel distensibility. Ultrasound examination may demonstrate colon wall thickening, and colonoscopy may reveal signs of narrowing or mucosal inflammation. Treatment consists of reducing enzyme dosing to less than 2500 lipase units per kilogram per meal when necessary. In the presence of sufficiently severe bowel obstruction, surgical resection may be warranted. For those patients not requiring surgery, longitudinal follow up for eventual stricture formation will be necessary.
Of interest, it seems that patients with cystic fibrosis may carry an increased risk for the development of celiac disease relative to the general population, as the coexistence of both conditions has been well-documented and the risk estimated at 0.45% of cystic fibrosis patients.15 Because the symptoms of celiac disease are primarily those of malabsorption, they may be attributed to cystic fibrosis, so the diagnosis requires a high degree of suspicion.
Inflammatory Bowel Disease
A number of cases of coexisting cystic fibrosis and inflammatory bowel disease have been reported, with estimates of the risk of inflammatory bowel disease complicating cystic fibrosis at 0.2% to 1%.16 The inflammatory bowel disease is usually Crohn's disease, with an incidence 17 times greater than controls.
Other Gastrointestinal Disorders
Of course, the individual with cystic fibrosis is at risk for common gastrointestinal disorders as well. Gastroesophageal reflux is a frequent problem, aggravated by factors such as increased work of breathing and medications that may decrease lower esophageal sphincter pressure. Peptic ulcer disease is commonly recognized and is treated the same as in the absence of cystic fibrosis. Of interest, persons with cystic fibrosis have a low frequency of pseudomembranous colitis despite frequent exposure to antibiotics for the treatment of pulmonary infections.17
From the earliest recognition of cystic fibrosis as a distinct disease entity, liver involvement has been noted. The frequency of liver disease in cystic fibrosis is difficult to estimate chiefly because it is difficult to identify precisely. No readily available clinical tool currently exists to reliably detect the earliest stages of cystic fibrosis-related liver involvement. This results in estimates of liver disease frequency in cystic fibrosis ranging from as low as 1.4% when insensitive methods such as the physical examination are used to more than 30% when the diagnosis is more aggressively pursued or when autopsy data are included.18 Broad surveys of cystic fibrosis patients in the United States and England probably provide the most reliable estimates of the magnitude of the problem: asymptomatic abnormal liver enzymes are seen in 12.9%; overt liver disease occurred in 4.2% to 8.7% of patients, with the higher rates occurring in adolescence and with a two- to threefold male preponderance; and frank cirrhosis occurred in 1.4% to 2.7%, also peaking in adolescence.19,20 Most liver involvement in cystic fibrosis is asymptomatic and may be slowly or not at all progressive. With patient survival now extending into the third and fourth decades, it remains to be seen whether early, mild liver abnormalities will become clinically important. For some patients, however, the clinical sequelae of advanced cirrhosis may be their major source of morbidity.
Liver disease correlates poorly with specific genotypes, although it does occur mostly in pancreaticinsufficient individuals. A history of meconium ileus or distal intestinal obstruction syndrome21 and specific histocompatibility antigens22 have been identified as additional risk factors.
Prolonged Neonatal Cholestasis
The earliest clinical syndrome of liver disease in cystic fibrosis is prolonged neonatal cholestasis, clinically indistinguishable from othet causes of conjugated hyperbilirubinemia in the newborn period. It occurs more commonly in infants also affected by meconium ileus and results from the inspissation of bile in the biliary tree. It is generally self-limited and does not indicate a higher risk of later liver disease. Its importance lies mainly in the need to distinguish this cause of neonatal cholestasis from others, such as biliary atresia, requiring specific intervention. Conversely, one must remember to consider die diagnosis of cystic fibrosis in all infants with prolonged cholestasis.
A much more common form of liver involvement in cystic fibrosis is steatosis, estimated to occur in up to 40% of patients.23 Severe degrees of fatty infiltration are typically associated with generalized malnutrition, such as may be present prior to diagnosis and appropriate enzyme supplementation. Although not a cause of major liver dysfunction in itself, experience with steatosis unrelated to cystic fibrosis would suggest that when it is prolonged, a small percentage of individuals will develop progressive fibrosis. Implementation of nutritional support is indicated and beneficial.
Focal Biliary Fibrosis
The pathognomonic hepatic lesion of cystic fibrosis is focal biliary fibrosis present in up to 50% of children dying beyond 1 year of age.24 As the name implies, focal areas of bile inspissation occur due to the underlying secretory defect in bile duct epithelium, resulting in local inflammation and fibrosis. At this early stage of involvement, the patient is generally asymptomatic. Eventually, liver involvement may become manifest in a number of subtle ways, including asymptomatic hepatomegaly or liver enzyme elevation. If these focal changes become widespread enough, multiiobular biliary cirrhosis ensues and may result in portal hypertension with its attendant complications of splenomegaly, hypersplenism, and esophageal varices.
It would obviously be desirable to identify early liver disease in cystic fibrosis, particularly because promising therapy is emerging. Liver enzymes, including aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase, should be followed at least annually in ail cystic fibrosis patients. Care should be taken on the physical examination to look for evidence of liver disease. Ultrasonography is useful in the identification of steatosis, biliary tract disease, and changes suggesting cirrhosis, portal hypertension, and varices. More sensitive methods of detecting early liver disease, including serum bile acid analysis and quantitative hepatobiliary scintigraphy, are currently under investigation.
There is growing evidence to support the treatment of cystic fibrosis-associated liver disease with ursodeoxycholic acid. This naturally occurring compound normally comprises only a minor fraction of human bile acids. When administered orally to patients with cystic fibrosis, the hydrophilic ursodeoxycholic acid is relatively enriched in the bile acid pool, displacing more hepatotoxic bile acids and also stimulating bile flow. Studies of ursodeoxycholic acid in doses of up to 20 mg/kg/day in small numbers of patients with cystic fibrosis and evidence of liver dysfunction have shown beneficial effects on liver enzymes and bile excretion as measured by hepatobiliary scintigraphy.25 Although it is not yet known what sustained effect such treatment may have on the progression of liver disease, given its good safety profile, ursodeoxycholic acid is likely to be used more widely and earlier in the course of liver disease. Selected cystic fibrosis patients with advanced liver disease and relatively mild lung disease have undergone liver transplantation and appear to have good outcomes similar to those for children transplanted for other indications.18
Other Hepatobiliary Disorders
A number of other hepatobiliary disorders are seen with increased frequency in cystic fibrosis (Table 1). Gallstones occur in approximately 12% to 27% of cystic fibrosis patients. Because the gallstones are comprised chiefly of calcium bilirubinate rather than cholesterol, they are not typically amenable to bile acid dissolution therapy and should be managed as in patients without cystic fibrosis.
Distal common bile duct stenosis was detected by hepatobiliary scintigraphy in a high percentage of persons with cystic fibrosis and evidence of liver disease,26 evidently the result of long-standing pancreatic inflammation and fibrosis leading to mechanical compression of the intrapancreatic distal common bile duct. Although the high frequency initially reported has not been substantiated, this diagnosis should be considered in the cystic fibrosis patient with liver disease and abdominal pain.
AN APPROACH TO COMMON CLINICAL PROBLEMS IN THE CYSTIC FIBROSIS PATIENT
The problems of enzyme-refractory diarrhea and liver enzyme abnormalities occur commonly enough in the cystic fibrosis patient that they deserve additional discussion regarding management.
If a cystic fibrosis patient has persistent diarrhea despite appropriate doses of pancreatic enzymes, further evaluation will be required. First, adequate compliance with the prescribed enzyme regimen should be ensured. This includes taking the proper dose of enzymes and the proper brand, as some generic products have been documented to be inferior.27 Enzymes must be stored in a cool, dry location and should be discarded at expiration as enzyme activity deteriorates with storage. Second, enzymes should be taken with all meals and snacks and may need to be divided into two doses if a meal is prolonged (half given at the beginning and half part way through the meal).6 Dietary irregularities, including episodic intake of high-fat foods and irregular meal schedules, also may require adjustments in routine enzyme dosing.
If diarrhea persists despite attention to the above measures, an empiric trial of gastric acid suppression with an H2 -receptor antagonist may be undertaken in an effort to create a less acidic duodenal environment.28 This will enhance enzyme delivery by facilitating dissolution of the pH-sensitive enteric coating of the microtablets, which begin to dissolve above pH 5.5 to 6.0. The typical duodenal pH in the patient with cystic fibrosis is frequently lower than this because of the lack of pancreatic bicarbonate secretion. K diarrhea persists after such a trial, it would be useful to document that the diarrhea is in fact due to fat malabsorption by a 72-hour fecal fat collection. Remember that patients with cystic nbrosis are still at risk for such common conditions as viral gastroenteritis, parasitic infestation, lactose intolerance, and nonspecific toddler's diarrhea due to excessive fruit juice consumption. If steatorrhea is documented despite consideration of the above issues, additional evaluation for celiac disease or Crohn's disease may be required.
Elevated Liver Enzymes
The finding of elevated liver enzymes in the patient with cystic fibrosis should prompt careful evaluation for the presence of liver disease. In addition to the hepatobiliary complications of cystic fibrosis mentioned above, one also must consider that unrelated infectious or metabolic diseases may be present. Physical examination should look specifically for hepatosplenomegaly, ascites, peripheral edema, cutaneous stigmata of liver disease, and the general nutritional state. Laboratory evaluation may need to include serology for infectious agents (hepatitis A, B, and C; cytomegalovirus; and Epstein-Barr virus), as well as tests for alpha^antitrypsin deficiency, Wilson's disease, or autoimmune hepatitis. Additional assessment of liver function will include the measurement of the prothrombin time and albumin; however, the interpretation of abnormal values can be confounded by poor nutritional status.
In most cases, ultrasonography of the liver and biliary tree should be performed. This test will provide useful information regarding the presence or absence of gallstones, steatosis, and ascites. Indirect evidence of cirrhosis and portal hypertension may be detected by nodularity of the liver, blood flow in the portal vein going away from the liver by Doppler, and the presence of dilated coronary veins or esophageal varices. Selected patients with bile duct dilatation may require endoscopie retrograde cholangiopancreatography to exclude bile duct stricture or sclerosing cholangitis. Percutaneous liver biopsy is not commonly performed in patients considered to have cystic fibrosis-related liver disease, such as focal biliary fibrosis or multilobular cirrhosis because of the patchy nature of the liver lesion and the likelihood of missing it with a random needle biopsy.
If liver enzymes remain elevated and alternative diagnoses have been excluded, some cystic fibrosis centers would undertake therapy with ursodeoycholic acid as described above in doses of approximately 20 mg/kg/day, while monitoring for improvement in the liver enzymes.
Cystic fibrosis is clearly a multisystem disease, with the potential for prominent gastrointestinal and hepatobiliary involvement. While the routine patient with pancreatic insufficiency may be easily managed with pancreatic enzyme and nutritional therapy, a large number of individuals with cystic fibrosis will present the clinician with gastrointestinal problems requiring additional thoughtful evaluation and treatment. Familiarity with the common gastrointestinal manifestations of cystic fibrosis and emerging therapies is necessary to provide the comprehensive care these patients deserve.
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3. Forstner OG, Durie PR. Cystic fibrosis. In: Walker WA, Durie PR, Hamilton JR, et al, eds. Pediatric Gastrointestinal Disease. 2nd ed. St Louis, Mo: Mosby; 1996:14661487.
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6. Borowitz DS, Grand RJ, Durie PR, Consensus Committee. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. J Pediatr. 1995;127:681-684.
7. Handwerget S, Roth J, Gordon P, et al. Glucose intolerance in cystic fibrosis. N Engl J Med. 1969;281:451-461.
8. Finkelstein SM, Wielinski CL, Elliott GR, et al. Diabetes mellitus associated with cystic flbrosis. J Pediatr. 1988;112:373-377.
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17. Winesect DE, Rhoads JM. Boat TF. Pseudomembranous colitis in a patient with cystic fibrosis. J Pediatr. Gastroenterol Nutr. 1994;18:244-246.
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24. Gaskin K. The liver and biliary tract in cystic fibrosis. In: Suchy FJ, ed. Liver Disease in Children. St Louis, Mo: Mosby; 1994:705-719.
25. Colombo C, Castellani MR, Balistreri WR et al. Scintigraphic documentation of an improvement in hepatobiliary excretory function after treatment with ursodeoxycholic acid in patients with cystic fibrosis and associated liver disease. Hepatology. 1992;15:677-684.
26. Gaskin KJ, Waters DLM, Howman-Giles R, et al. Liver disease and common-bileduct stenosis in cystic fibroiis. N Engl J Med 1988;318:340-346.
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28. Durie PR, Bell L, Linton W, et al. Effect of cimeridine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis. Gut 1980;21:778-786.
Gastrointestinal Manifestations of Cystic Fibrosis*
Pancreatic Enzyme Therapy in Cystic Fibrosis*