Journal of the Royal Society of Medicine Supplement No. 18 Volume 85 1992 13
Gastrointestinal complications in cystic fibrosis
J M Littlewood FRCP DCH Regional Cystic Fibrosis Unit, St James' University Hospital, Beckett Street, Leeds LS9 7TF Keywords: gastro-oesophageal reflux; peptic ulcer; Helicobacter pylori, meconium ileus; pancreatitis
The majority of cystic fibrosis (CF) individuals have pancreatic insufficiency which, if not treated, will lead to a variety of gastrointestinal symptoms and signs associated with intestinal malabsorption. With modern pancreatic enzyme replacement therapy, the majority are well controlled. However, a minority have persisting gastrointestinal problems despite large doses of pancreatic enzymes. In some, the malabsorption persists for a variety of reasons which have been reviewed elsewhere'-3. In others there are reasons unrelated to their CF4 5. These alternative or additional explanations should always be considered even when it appears likely that CF is directly responsible for the gastrointestinal symptoms.
Oropharynx Histological abnormalities have been described in the salivary glands and these glands may be enlarged6. These changes have little practical relevance in the pathogenesis of the malabsorption but the secretion of amylase is said to be increased. Lingual lipase may contribute to the apparent slight residual ability to digest fat even in the absence of pancreatic lipase.
Oesophagus Vomiting is a relatively common problem in nonscreened CF infants who present symptomatically and may be the main presenting problem. There is an increased frequency of gastro-oesophageal reflux (GOR) in CF7,8. A recent study identified inappropriate relaxation of the gastro-oesophageal sphincter as the major cause of their reflux9. Severe GOR and associated symptomatic oesophagitis may prove a major problem at any age'0. Symptoms of reflux may be controlled by standard medical treatment including thickening feeds-in CF with cereal to enhance energy intake and a change to more solid food generally. Alkalis and H2 receptor antagonists should be used if there are any signs suggesting oesophagitis. Cisapride is of some value and was effective in controlling the reflux in 8 of 10 CF infants in one study". In the young CF patient with reflux and vomiting sufficient to interfere with weight gain, a fundoplication may be required. In addition to the usual anti-reflux treatment, a more aggressive approach to the chest infection with high doses of intravenous antibiotics may lead to a significant reduction in vomiting and improvement of the oesophagitis. It is our impression that GOR is of clinical significance in a minority of young CF patients but becomes of increasing importance in older patients with more severe chest problems when GOR may result in severe oesophagitis and eventual oesophageal stricture. Patients with GOR had worse lung function
than those with negative barium studies in the experience of one clinic'2.
Stomach No specific histological abnormalities have been described in the stomach. Although delayed gastric emptying has been suggested, a study using epigastric impedance recording, a non-invasive, non-isotopic technique, failed to show prolongation of gastric emptying of clear fluids in CF patients compared with controls and an insignificant difference with low fat
liquids'3. Peptic ulcer is usually a result of severe physical stress rather than a specific problem associated with the CF'4. In one autopsy series of 146 patients, a peptic ulcer was present 12(8%)15. In our CF children and adults peptic ulcer does not appear as a problem. However, although the gastritis due to Helicobacter pylori has been reported to be no more common in 179 CF individuals (11% positive) than 170 controls (16% positive)'6, preliminary results in the Leeds clinic suggest there may be an increased prevalence of Helicobacter pylori in CF (Crabtree J, unpublished observations). The adverse effects of multiple drugs on the gastric mucosa should be considered in patients where vomiting is a problem and gastroscopy may reveal a nonspecific gastritis.
Duodenum and small bowel The small bowel villi are rather taller than normal. Electrical abnormalities of the small bowel mucosa have been described and appear to be related to the basic defect in the epithelial cells17. An enhanced response to amiloride has been observed in the colonic epithelium of CF infants although there is no difference in the resting potential difference; the defect in chloride secretion may be important in the aetiology of distal intestinal obstruction syndrome'8. The duodenal pH is low as reduction in pancreatic bicarbonate secretion is an early and severe feature. The acidic conditions in the upper small bowel lead to bile salt precipitation and defective lipid solubilization19,20. However, although the duodenal and upper jejunal pH is low, most of the small bowel is at a pH 6 or more21 which permits the release of the enzymes from microsphere pancreatin preparations22. The small bowel transit time is prolonged in CF compared to controls21. Meconium ileus Some 10-15% of CF infants present with intestinal obstruction due to meconium ileus (MI3. Of the 386 CF patients referred to Leeds for assessment, 69 (17.9%) had presented with neonatal meconium ileus.
14 Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992
The meconium of CF infants has a decreased water content, electrolytes, except calcium, and proteolytic activity but increased protein. In infants with MI, the ileum and colon contain pellets of inspissated mucous. The calibre of this bowel is small-the unused microcolon. Proximally, the small bowel is dilated and contains thick, sticky meconium. The dilated bowel may undergo volvulus with perforation and peritonitis. Antenatal perforation causes meconium peritonitis with calcification and antenatal volvulus causes ileal atresia, again frequently associated with meconium peritonitis. Although usually associated with CF and pancreatic insufficiency, MI may occur without pancreatic insufflciency24 and in conditions other than CF25. The diagnosis may be suggested by the presence of loops of bowel demonstrating increased echogenicity on ultrasound in the first trimester26 although the reliability ofthis observation has been questioned. In the neonatal period there are symptoms and signs of intestinal obstruction. Loaded loops of bowel may be palpable. The rectum is tight on examination. Abdominal X-ray shows dilated loops of bowel with a ground glass appearance (there is no air in the meconium). Fluid levels are often not demonstrable because of the consistency of the bowel contents. Calcification of intra luminal contents sometimes occurs. Contrast enema usually shows microcolon often with filling defects of the mucous pellets. The differential diagnosis includes Hirschprung's disease, intestinal volvulus, ileal atresia and other surgical emergencies. A significant proportion of infants with MI have peritonitis, volvulus or atresia. A skilled paediatric radiologist can relieve the obstruction with serial gastrografin enemas in
Table 1. Abdominal symptoms and signs in 100 CF patients
Appetite Abdominal pain Fullness Bowels/day Abnormal stools Vomits Distension Palpable mass Liver+spleen
normal 24, good 48, mod 17, small 11 11 (none severe) 9 (2 severe) 1.99 11 4 (occasional in all) 2 4 9 (liver+spleen 5, liver 2, spleen 2)
uncomplicated meconium ileus27. Secure intravenous access, adequate hydration and close monitoring are essential. In case of complications, urgent rsuscitation and surgery may be required so this mode of treatment is only appropriate in a centre with facilities for neonatal surgery. Over -recent years, the outlook for these infants has improved and is similar to that of other CF
infants23MA289. Sequelae of neonatal surgery After the newborn period there may be late complications resulting from loss of resected intestine or the development of stricture or band obstruction at the site of the neonatal anastomosis (Figure 1). Despite the occasional later surgical complications, there is no significant excess of gastrointestinal problems in later childhood and the frequency ofbowel symptoms and nutritional state is similar to those of patients presenting with malabsorption or chest problems (Table 1). CF individuals who have persisting bowel symptomsdespite aeuate pancreatic enzyme therapy should be thoroughly investigated, particularly if they have had neonatal surgery to ensure there is no residual anatomical abnormality.
Dllt intestinal obstruction syndrome (meconium ileus equivalent)_ The distal intestinal obstruction syndrome (DIOS) is characterized by repeated attack of complete or partial intestinal obstruction occurring in a CF individual3s. It has been reported that some 10-47% CF individuals suffer from some degree of recurrent intesti-nal obstruction. It does not appear to be more common in those who presented originally with meconium ileus31. In our clinic 111 of-patients comphlin ofoccasional abdominal pain from any cause and classical DIOS is a rarity (Table 2). In patients with )DIO0, there may be a history of increasing -constipation and inadequate intake of pancteatic supplements suggested by significantly less than average doses or bypoor patient compliance. the presence of a low faecal chymotrypsin in the Table 2. Abdominal pain and palpable mass in 369 CF patients referred to Leeds over the past 11 years T' Presentation
Meconium ileus
16spiatoiy i
.P
II.. ,
i
..
Figure 1. Severe ileal distettion proximal to a stricture atthe site of neonatal intestinal anastomosis after meconium-ieus surgery
Malabsorption S-rin CF sibling
Pain
Mass
26/69 (37.7%) 33/89 (39.0%) 86/184 (47.0%) 1/23 (4.0%) 8/24 (30.0%)
5/69 (7.2%) 5/85 (5.9%) 11/184 (6.0%) 0123 (0.0%) I-
2/24 (8.3%)
Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 15
presence of an apparently reasonable enzyme intake suggests non compliance. Inspissated intestinal contents present in the distal ileum and proximal colon can often be palpated as masses in the right iliac fossa. In some patients there are the classical signs of small bowel obstruction with pain, distension, constipation and bilious vomiting. In CF patients who have DIOS it may be particularly difficult to identify the presence of other conditions such as appendicitis, intussusception, intestinal volvulus, Crohn's disease, small bowel perforation, fistula or ovarian conditions3233.The varying prevalence of the complication supports the view that a chronic under treatment with pancreatic enzymes is important in the development of DIOS3. In Leeds the condition is rare. Intestinal absorption is monitored regularly by dietary assessments and faecal fat estimations and those with significant steatorrhoea (less than 85% absorption of dietary fat intake) have their dose ofpancreatic enzyme increased even if they have no symptoms3. In the few patients who do suffer from recurrent DIOS, compliance- with enzyme taking appears to be a major factor in some but occasionally there is no obvious explanation for their problem. In one series. the diabetes mellitus present in some of the patients and possibly mild dehydration may have been a contributory factor35. Opiate addiction has been implicated as a contributory . factor36. Ultrasound examination may be helpful in identifying the obstructing masses but cannot be relied upon to exclude other causes of pain and obstruction such as intussusception and appendicitis. Investigations should include a serum amylase and erect and supine abdominal radiographs. If the condition is not responding to medical treatment a contrast enema should be performed (see below). Computerised tomography has been recommended to reduce the likelihood of unnecessary surgery and to monitor the treatment of the condition37. Patients with more resistant and prolonged symptoms may be unwell and dehydrated and requiLre urgent intravenous rehydration and exclusion ofother surgical conditions. For patients with mild symptoms of colicky pain and perhaps with a mass, one or more doses of oral gastrografin (diatrizoate) with fluid usually relieves the situation in hours"34. We use the recommended doses of 100 ml of gastrografmi in 400 ml of water or fruit juice for patients over 8 years and 50 ml gastrografin and 200 ml fluid for younger patients; then half dose can- be given daily until clear. Gastrografin can be used as an enema using 100 ml up to three times daily. It is important to maintain adequate hydration. Some prefer to use oral N-acetyl cysteine using a solution of 10-20 g in 100 ml and giving 10 ml three times. daily or-a an- enema uaing 50 ml of the solution with 50 ml of water.. Acute hypomagnesaemia. has been described as a complication of treatment38. An increasingly -popular treatment is the oral administration of large volumes of a balanced electrolyte intestinal lavage. solution39-4l. We have found Klean-Prep a convenient ready mixed preparation. Adults may drink the solution but -children usually require a nasoga tube to .aqhieve. the 20-30 ml/kg body weight per hour required(max-one litre/hour). Usually 2-3 litres of the solution are required for a child and 5-6 litres .for an adult.
Although-the reported overall benefits ofcisapride in CF42 have not been confirmed in a small controlled trial43, the drug may help those with persisting recurrent-episodes of DIOS and/or constipation41. The incidence of DIOS does not appear to have increased following relaxation of fat restriction after the introduction of acid resistant pancreatic supple.ments. Compliance with taking pancreatic enzymes is a major problem particularly in older patientsthis at a time when growth results in a relative decrease in the number of enzyme capsules per kilogram of body weight". Thus, a check on the adequacy of and compliance with pancreatic replacement therapy should follow an acute episode of DIOS. Regular doses of oral gastrografm (perhaps every weekend) have proved effective in some patients with more chronic low grade symptoms which persist even after improving intestinal absorption.
Constipation and acquired megacolon Although many CF patients have abdominal pain due to DIOS some patients have primarily an acquired megacolon syndrome with chronic faeeal retention45; there is not necessarily 'the passage of hard and infrequent stools'. There may be either reduced bowel frequency and occasionally severe overloading.even resulting in soiling. Distal colonic obstruction severe enough to require laparotomy has been described46. There is usually impressive evidence of colonic faecal overloading on the abdominal radiograph. These patients have often been diagnosed late or received inadequate treatment with pancreatic enzymes resulting in chronic faecal accumulation. If such patients are suddenly given increased doses of pancreatic enzymes to control the chronic malabsorption which most of them have, they .may develop severe constipation which requires vigorous laxative treatment similar to that used for DIOS-which may also be present. Treatment, in non-acute cases, is first to ensure that absorption is adequately controlled by gradually increasing the pancreatic enzyme supplement until the faecal fat absorption is reasonable (more than 85%) and also treat with laxatives-either regular lactulose, Senokot (senna), gastrografin (diatrizoate) or even balanced electrolyte intestinal lavage solution. Abdominal radiograph to determine the degree of faecal overloading is a helpful addition to history and examination not only in diagnosis but also in determining effectiveness of the treatment. Cisapride has proved helpful in some of these patients4l, as it is in non CF individuals who have severe constipation47.
Appendicitis In -a recent review of 1220 CF patients, a total of 60 (4.9%) patients had undergone appendicectomy. The authors ooncluded that the spectrum of appendiceal disease, in CF varied from simple mucus distention to classical acute appendiiis with perforation. Pain from a non-in"flamed distended appendix represented a distinct syndrome in (CF patients". In a review of five cases of appendicitis, the high incidence of abcess formation in CF patit was noted altfhough the incidence of appendicitis as such was relatively low in CF individuals. In 49 of 51 autopsied CF patients the mueosa -was hyperplastic, and the glands distended with eoainophilic material49.'In a recent report of nine patients.from the Toronto clinic,
16 Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992
eight had abscesses and in four operation was delayed for more than 3 days50. Appendicitis should be considered in any CF patient with suggestive symptoms particularly if the barium enema shows extrinsic compression of the caecum. Ultrasound, CT and gallium scans are of limited value3350. Even with present day investigations, abdominal tenderness remains one of the most important signs of abscess51. Intussusception of the appendix has been described and is an alternative explanation for cramping lower abdominal pain in the CF patients52.
Intussusception Intussusception has been mentioned already but it should be emphasized that the condition should always be suspected in any patient with colicky abdominal pain even if previously affected distal ileal obstruction syndrome. It has been estimated that 1% of CF patients have intussusception, but this report was before microsphere preparations were available53. The main clinical features were colicky abdominal pain (77%), a palpable mass (68%), vomiting (57%) and rectal bleeding (23%). Not all would agree that ultrasound is 'a reliable non-invasive method to confirm or exclude intussusception'54 despite the characteristic bull's eye appearance55. In our experience abdominal ultrasound may miss intussusception in CF patients and a contrast enema should be an early investigation and will usually suggest the diagnosis56. The intussusception may be chronic in CF patients as in one case reported54. A suggested approach to the management of a CF patient with severe colicky pain and a right iliac fossa mass has been proposed by Smith et al.33 An initial contrast enema should be performed to exclude intussusception and may also be therapeutic. If not effective, balanced electrolyte intestinal lavage solution therapy should be used, proceeding if necessary to an ultrasound and/or CT scan followed by repeat lavage. Finally laparotomy should be considered. We would support the importance of a contrast enema at early stage in an attempt to rule out intussusception. We have also failed to identify intussusception by ultrasound examination. Increasing local tenderness and the patient's general condition are also of paramount importance in deciding on the need for surgical intervention. Pancreatitis Histological abnormalities of the pancreas are present in all CF infants at birth57. In the majority of patients there is reduced secretion of both pancreatic enzymes and bicarbonate. A minority of CF patients (between 5 and 15% depending on the clinic) do not have steatorrhoea as there is sufficient pancreatic function to control intestinal absorption58. A very occasional CF patient has pancreatic calcification which does not appear to have a particular clinical association59. There have been two examples of pancreatic calcification in the 386 patients
referred
to Leeds.
Pancreatitis is a well described complication in older CF patients who have some residual pancreatic function60 61. Cystic fibrosis should be considered in all patients with acute or relapsing pancreatitis even if there are no other features suggesting the diagnosis. Pancreatic serum enzymes, usually low in CF, are raised in the patients who have pancreatitis. Pancreatic ultrasound, usually abnormal by mid
childhood, but may be normal in pancreatic sufficient
patients"4. Cows' milk intolerance Vomiting, failure to thrive or persisting bowel problems may be due to cows' milk intolerance (CMI). The symptom triad of hypoproteinaemia, oedema and anaemia has been attributed to CMI63. More recently CMI has been proved by serial jejunal biopsies in CF infants and it is important to consider this possibility in any CF infant who is failing to thrive"'. The resolution of diarrhoea and improved absorption observed in some CF infants following a change to a cows' milk free formula such as Pregestimil may be related to CMI. However, clinical food allergy and intolerance is unusual in older CF patients even though many are atopic; it has been suggested that antigen absorption may be impaired in CF as evidenced by the fewer than expected positive RASTs to foods65. Coeliac disease Coeliac disease is well documented as occurring in CF patients66'67 and appears to be more common than in the general population. Recently five CF patients with coeliac disease have been reported in a CF population of 1100 (1 in 220). Coeliac disease was diagnosed in these patients following investigation of persisting clinical and biochemical evidence of malabsorption despite apparently adequate pancreatic supplements. All had subtotal villous atrophy of the jejunal mucosa which responded to a gluten free diet and histological relapse after subsequent gluten challenge68. Although gliadin antibodies may prove of value in identifying CF individuals at risk for coeliac disease, their reliability has not been evaluated in CF. Therefore a jejunal biopsy should be included in the investigations of any CF patient who has persisting bowel symptoms and malabsorption despite apparently adequate pancreatic enzyme treatment.
Giardiasis In one USA series of CF patients an impressive number were infected with Lamblia giardia. A cross sectional study, using a sensitive ELISA method for identification, showed that 28% of CF patients were positive for giardia compared to 6% of controls69. Although we have diligently searched for giardiasis in many CF patients with persisting bowel problems, admittedly not using a sensitive ELISA test, we have failed to identify the protozoan as a significant problem in our CF patients. However, there have been isolated reports of giardiasis affecting CF patients in this country4. Crohn's disease Crohn's disease in CF patients has been reported on a number of occasions and can prove difficult to diagnose before laparotomy, which may itself be delayed, the symptoms being attributed to DIOS. Before the mid 80s, when the acid resistant pancreatic preparations became generally available in the UK, it is likely that all but the most florid examples of Crohn's disease were attributed to the malabsorption, unless the diagnosis had been made at laparotomy. The increasing frequency of reports of Crohn's disease in CF patients may be related to their increased survival70-74. It has been suggested that inflammatory bowel disease is more likely to develop after meconium
Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 17
ileus75 and the increased survival of these infants may be relevant76. Also the improved recognition of Crohn's disease in children and adolescents by the availability and more frequent resort to fibreoptic endoscopy may have permitted more accurate histological diagnosis in some cases. It is sound advice that 'any patient with CF who does not have an obvious explanation for failure to thrive or growth failure as a result of advanced pulmonary disease or who fails to respond to treatment for pancreatic insufficiency needs a full work-up that includes demonstration of the anatomical status of the intestinal tract'74 75. One would stress that the investigations would include biopsies of the gastric, duodenal and colonic mucosae for histology. There has been no CF patient recognized as having Crohn's disease in over 400 CF patients known to the Leeds clinic. Rectal prolapse There is a definite but variable association with rectal prolapse recognized for many years in the untreated CF patient77. Rectal prolapse occurred in 18.5% of one series of CF patients, usually in the second or third years and commonly before adequate pancreatic replacement therapy was started78. The complication is rare after the age of 5 years. In patients referred to Leeds, 57/386 (14.8%) had experienced at least one episode ofrectal prolapse. The frequency varied with the mode of presentation being 11.5% (10/69) in those presenting with meconium ileus, 20.1% (37/184) in those presenting with gastrointestinal signs and 11.8% (10/85) in those presenting with respiratory symptoms. Further prolapse is usually prevented by control of the malabsorption and improved nutrition following the start of treatment. In a recent series of children presenting with rectal prolapse only six (11%) had cystic fibrosis79. Nevertheless a sweat test should be performed in any children with this problem. Intra abdominal malignancy As the survival of CF individuals improves, there have been a number of reports of malignant disease. Adenocarcinoma of the ileum has been reported in four patients80. Another presented as clostridial myonecrosis81. Bowel carcinoma may mimic meconium ileus equivalent82'83. Carcinoma84 and adenocarcinoma85'88 of the pancreas have been described and carcinoma of the extrahepatic biliary system87. The increasing frequency of these reports have been advanced as a reason for routine CF postmortem examinations. Pneumatosis intestinalis Intramural gas is described in CF patients with severe pulmonary disease. The condition was found in 41 of 491 patients coming to autopsy in Boston88. We have no experience of the condition in over 400 CF patients. Twenty-four died but few have a postmortem
examination. Conclusion Abdominal symptoms and signs are infrequent in those patients whose intestinal absorption is well controlled. The CF patient may, of course, suffer from any of the intra-abdominal conditions which occur in the non-CF individual. It is important that these are considered both as the main cause of the patient's
Table 3. Investigation ofpersisting abdominal symptoms
Review diet, faecal fat and percentage absorption Check enzyme therapy and faecal chymotrypsin Consider whether medication causing symptoms Urinalysis (renal ultrasound if urine abnormal) Full blood count, erythrocyte sedimentation rate or plasma viscosity Urea, electrolytes, amylase, liver function tests Helicobacter pylori antibodies Abdominal radiograph for faecal loading Check for gut infection and giardiasis Hydrogen breath test for small bowel infection Ultrasound gallbladder, bile ducts and pancreas Radiograph contrast studies to check gut anatomy Exclude coeliac disease and food intolerance Gastroscopy, colonoscopy with biopsies Consider emotional factors Surgical opinion ? laparotomy
symptoms and also as an additional complication of an existing CF-related disorder, eg appendicitis or intussusception in a patient who already has distal ileal obstruction. The improved longevity of patients and the better control of their malabsorption, and its associated symptoms, have permitted more frequent recognition of gastrointestinal complications and additional disorders. A CF patient with persisting abdominal symptoms and signs, despite adequate doses of pancreatic enzymes, deserves full gastrointestinal investigation (Table 3) to exclude the other disorders which are unrelated to the CF yet amenable to appropriate treatment. Acknowledgments: The author thanks Mr John Beck for sharing his great experience in managing infants with meconium ileus and Dr Steve Conway for helpful discussion and suggestions. References 1 Park RW, Grand RJ. Gastrointestinal manifestation of cystic fibrosis: a review. Gastroenterology 1981;81:1143-61 2 Durie PR, Pencharz PB. A rational approach to the nutritional care of patients with cystic fibrosis. J R Soc Med 1989;82(suppl 16):11-20 3 Littlewood JM. Pancreatic enzymes in cystic fibrosis. In: Lankisch PG, ed. Pancreatic enzymes in health and disease. Berlin: Springer-Verlag, 1991:177-89 4 Baxter PS, Dickson JA, Variend S, Taylor CJ. Intestinal disease in cystic fibrosis. Arch Dis Child 1988;63:1496-7 5 Dalzell AM, Heaf DP, Carty H. Pathology mimicking distal ileal obstruction syndrome in cystic fibrosis. Arch Dis Child 1990;66:540-1 6 Barbero GJ, Sibinga MS. Enlargement of submaxillary salivary gland in cystic fibrosis. Pediatrics 1962;29: 788-93 7 Bendig DW, Wagner ML, Harrison GM, et al. Complications of gastroesophageal reflux in cystic fibrosis. J Pediatr 1982;100:536-40 8 Scott RB, O'Laughlin EV, Gall DG. Gastroesophageal reflux in patients with cystic fibrosis. J Pediatr 1985;106:223-7 9 Cucchiara S, Santamaria F, Andreotti MR, et al. Mechanisms of gastro-oesophageal reflux in cystic fibrosis. Arch Dis Child 1991;66:617-22 10 Feigelson J, Girault F, Pecau Y. Gastroesophageal reflux and esophagitis in cystic fibrosis. Acta Paediatr Scand 1987;76:989-90
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11 Dab I, Malfoot A. Gastro-oesophageal reflux: a primary defect in cystic fibrosis. Scand J Gastroenterol Suppl 1988;143:125-31 12 Stringer DA, Sprigg A, Joudis E, et aL The association of cystic fibrosis, gastroesophageal reflux, and reduced pulmonary function. Can Assoc Radiol J 1988;39: 100-2 13 Smith HL, Hollins GW, Booth IW, Weller PH. Gastric emptying of liquids in cystic fibrosis. 16th European working group for cystic fibrosis. Prague, 1989: 83 14 Aterman K. Duodenal ulceration and fibrocystic disease of the pancreas. Am J Dis Child 1961;101:210 15 Oppenheimer EH, Esterley JR. Pathology of cystic fibrosis. Review of the literature and comparison with 146 autopsied cases. Perspect Pediatr Pathol 1975;2:241-78 16 Przyklenk B, Bauerfeind A, Bertele-Harms RM, Harms KH. The significance of Helicobacter pylori in patients with cystic fibrosis. 17th European cystic fibrosis conference. Copenhagen. 1991. Poster No 72:85 17 Baxter PS, Wilson AJ, Read NW, Hardcastle J, Hardcastle PT, Taylor CJ. Abnormal jejunal potential difference in cystic fibrosis. Lancet 1989;i:464-6 18 Gowen CW, Gowen MA, Knowles MR. Colonic transepithelial potential difference in infants with cystic fibrosis. J Pediatr 1991;118:412-15 19 Zentler-Munro PL, Fitpatrick WJF, Batten JC, Northfield TC. Effect of intrajejunal acidity on aqueous phase bile acid and lipid concentration in pancreatic steatorrhoea due to cystic fibrosis. Gut 1984;25.:500-7 20 Zentler-Munro PL. Pancreatic insufficiency and cystic fibrosis. Curr Opin Gastroenterol 1989;5:706-10 21 Gilbert J, Kelleher J, Littlewood JM, Evans DF. Ileal pH in cystic fibrosis. Scand J Gastroenterol 1988; 23(suppl 1):132-4 22 Littlewood JM, Kelleher J, Walters MP, Johnson AW. In vivo and in vitro studies of microsphere pancreatic supplements. J Pediatr Gastroenterol Nutr 1988;7 (suppl 1):S22-S29 23 Rescorla FJ, Grosfeld JL, West KJ, Vane DW. Changing pattern of treatment and survival of neonates with meconium ileus. Arch Surg 1989;51:34-48 24 Lands L, Zinman P, Wise M, Kopelman H. Pancreatic function testing or meconium ileus in cystic fibrosis: two case reports. JPediatr Gastroenterol Nutr 1988;7:276-9 25 Noblett H. Meconium ileus. In: Ravitch M, Welsh K, Benson C, et aL eds. Pediatric surgery. Chicago: Year Book Medical, 1979: 943 26 Benacerraf BR, Chaudhury AK. Echogenic fetal bowel in the third trimester aated with- meconium ileus secondary to cystic fibrosis. A case report. JReprod Med 1989;34:299-300 27 Noblett HR. Treatment of uncomplicated meconium ileus by gastrografin enema: a preliminary report. J Pediatr Surg 1969;4:190-7 28 Caniano DA, Beaver BL. Meconium ileus: a fifteen-year experience with forty-two neonates. Surgery 1987; 102:699-703 29 Dinwiddie R, Spitz L, Kiely E. Current management ot meconium ileus. 16th European working group for cystic fibrosis. Prague, 1989: 89 30 Jensen KG. Meconium ileus equivalent in a 15 year old patient with mucoviscidosis. Acta Pediatr Scand 1962; 51:344-8 31 Rosenstein BJ, Longbaum TS. Incidence of distal intestinal obstruction syndrome in cystic fibrosis. J Pediatr Gastroenterol Nutr 1983;2:299-301 32 Weller PH, Wiliams J. Clinical features, pathogenesis and management of mecomum ileus equivalent. JR Soc Med 1986;79(suppl 12):36-7 33 Smith HLL, Weller PH, Gornall P, Chapman 5, Jones TJ. Pitfalls in the diagnosis of appendix abscess in cystic fibrosis. J R Soc Med 1989;829(suppl 16):564-6 34 O'Halloran SM, Gilbert J, McKendrick DM, Cart HML, Heaf D. Gastrografin in acute meconium ileus equivalent. Arch Dis Child 1986;61:1128-30 35 Hodson ME, Mearns MB, Batten JC. Meconium ileus
equivalent in adults with cystic fibrosis. BMJ 1976; ii:790-1 36 Koletzko S, Stringer DA, Cleghorn GJ, Durie PR. Lavage treatment of distal intestinal obstruction syndrome in children with cystic fibrosis. Pediatrics
1989;83:727-33 37 Moody AR, Haddock JA, Given-Wilson R, Adam EJ. CT monitoring of therapy for meconium ileus. JComputer Assisted Tomography 1990;14:1010-12 38 Godson C, Ryan MP, Brady HR, Bourke S. Acute hypomagnesaemia complicating the treatment of meconium ileus equivalent in cystic fibrosis. Scand JGasroenterol Suppi 1988;143:140-50 39 Cleghorn GJ, Forstuer GG, Stringer PA,-Durie PR. Treatment of distal intestinal obstructionsyndrome in cystic fibirsis with a balanced intestinal lavage solution. Lancet 1986;i:8-11 40 Davidson AC, Harrison K, Steinfort CL, Geddes DM. Distal intestinal obstruction in cystic fibrosis treated by oral intestinal lavage, and a case of recurrent obstruction despite normal pancreatic function. Thorax 1987;42:538-41 41 Koletzko S, Corey M, Ellis L, Spino M, Stringer DA, Durie PR. Effects of cisapride in patients witlx cystic fibrosis and distal intestinal obstruction. J Pediatr
1990;117-:815-22 42 Prinsen JE, Thomas M. Cisapride in cystic fibrosis. Lancet 1985;i:512-13 43 Smith HL, Handy DJ, Weller PH, Booth IW, Cisapride and cystic fibrosis. Lancet 1989;i:338 44 Andersen HD, Hjelt K, Waever- E, Overgaard K. The age-related incidence of meconium ileus equivalent in a cystic fibrosis population: the impact of high energy intake. J Pediatr Gastroenterol Nutr 1990;11:356-60 45 Rubinstein S, Moss R, Lewiston N. Constipation and meconium ileus equivalent in patients with cystic fibrosis. Pediatrics 1986;78:473-9 46 Apelgmen KN, Yuen JC, Distal colonic impaction requiring laparotomy in an adult with cystic fibrosis. J Clin Gastroenterol 1989;11:687-90 47 Murray RD, Ulysses B, Li K. Juhling McClung H, Heitlinger L, Rehm D. Cisapride for intractable constipation in children: observations from an open trial. J Pediatr Gastroenterol Nutr 1990;11:503-8 48 Coughlin JP, Gauderer MW, Stern RC, Doershuik CF, Izant RJ, Zollinger RM. The spectrum of appendiceal disease in cystic fibrosis. JPediatr-Surg 1990;2:835-9 49 McCarthy VP, Mischler EH, Chernick MS, Di Sant'Agnese P. Appendiceal abscess in cystic fibrosis. Gastroenterology 1984;86:564-8 50 Shields MD, Levison H, Ris8man JJ, Durie PR, Canny GJ. Appendicitis in cystic fibrosis. Arch Dis child
1990;-6:307-10 51 Dobrin PB, HeerGully P, Greenlee HB, et aL Radiologic diagnosis of intraabdominal abscess. Do multiple tests help? Arch Surg 1986;121:41-6 *52 McKintosh JC, Mroczek EC, Baldwin C, Mestre J. Intussusception of the appendix in a patient with cyatic fibrosis. J Pediatr Gastroenterol Nutr 1990;11:542-4 53 Holsclaw D, Rocmans C, Shwachman H. Intuasusception in patients with cystic fibrosis. Pediatrics 1971;48:51-8 54 Webb-AK, Khan A. Chronic intussusception in a young adult with cystic fibrosis.- J R- Soc Med 1989;8a(suppl
16):47-8 55 Mulvihill DM. Ultrasound findings of chronic intussuseption in a patient with cystic fibrosis. J Ultrasound Med 1988;7:353-5 56 Holmes M, Murphy V, Taylor M, Denham B. Intussusoption in cystic fiboi. ArhDis Child 1991;#6:726-7 57 Imnie J, Fagan D, Sturgess J. Quantitative evaluation of the-development of the exocrine pancreas in'CF and control infants. Am J Pathol 1979;9B5:697-707 58 D)ure PR, Forstner GG. Pathophysiology of the exocrine pancreas in cystic fibrosis. JR Soc Med 1989;82suppl
i6):2-10
Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 19 59 Liu P, Daneman A, Stringer D, Durie PR. Pancreatic cysts and calcification in cystic fibrosis. J Can Assoc Radiol 1986;37:279-81 60 Shwachman H, Lebenthal E, Khaw K. Recurrent acute pancreatitis in patients with cystic fibrosis with normal pancreatic enzymes. Pediatrics 1975;55:86-94 61 Gross V, Schoelnerich J, Denzel K, Gerok W. Relapsing pancreatitis as initial manifestation of cystic fibrosis in a young man with cystic fibrosis. Int J Pancreatology 1989;4:21-228 62 Wilson-Sharp RC, Irving HC, Brown RC, Chalmers DM, Littlewood JM. Ultrasonography of the pancreas, liver, and biliary system in cystic fibrosis. Arch Dis Child 1984;59:923-6 63 Skopnik H, Heinman G. Manifestation of intolerance to cow's milk protein in mucoviscidosis with the symptom triad of hypoproteinaemia, edema and anaemia. Klin Padiabr 1987;199:453-6 64 Hill SM, Phillips AD, Mearns M, Walker-Smith JA. Cow's milk sensitive enteropathy in cystic fibrosis. Arch Dis Child 1989;64:1251-5 65 Ferguson A, Merrett TG, Littlewood JM, Bolderson I. IgE antibodies to foods are not a feature of cystic fibrosis. Hum Nutr:Clin Nutr 1986;40C:255-8 66 Goodchild MC, Nelson R, Anderson CM. Cysticfibrosis and coeliac disease: coexistence in two children. Arch Dis Child 1973;48:684-91 67 Taylor B, Sokel G. Cystic fibrosis and coeliac disease. Arch Dis Child 1973;4*:692-6 68 Valletta EA, Mastella G. Incidence of coeliac disease in a cystic fibrosis population. Acta Paediatr Scand 1989;78:784-5 69 Roberts DM, Craft JO, Mather FJ, Davis SH, Wright JA. Prevalence of giardiasis in patients with cystic fibrosis, J Pediatr 1988;112:555-9 70 O'Connor J, Lawson J. Fibrocystic disease of the pancreas and Crohn's disease. BMJ 1972;4:610 71 Euler AR, Ament ME. Crohn's disease-a cause of arthritis, oxalate stones and fistulae in cystic fibrosis. West Med J 1976;125:315-17 72 Ojeda VJ, Levitt S, Ryan G, Laurence BH. Cystic fibrosis. Crohn's colitis and adult meconium ileus equivalent. Dis Colon Rectum 1986;29:567-71 73 Behrens R, Segerer B, Bowing B, Bender SW. Crohn's disease in cystic fibrosis. J Pediatr Gastroenterol Nutr
1989;9:528-31
74 Lerner A, Gal N, Mares AJ, Maor E, Iancu TC. Pitfall in the diaguosis of Crohn's disease in a cystic fibrosis pAtioi. J PI4diatr Gtroenterol Ntsfr 1990;12:369-71 75 Lloyd-Still JD. Cystic fibrosis, Crohn's disease, biliary abnormalities, and cancer. JPediatr Gastroenterol Nutr 1990;11:434-7 76 Maboguje OA, Goldthorn JF, Wang CI, Hossein Mahour G. Colonic polyps and coloduodenal fistula: unusual complications in a patient with cystic fibrosis. Surgery 1981;90:114-16 77 Kulczycki LL, Shwachman H. Studies in cystic fibrosis of the pancreas: occurrence of rectal prolapse. N Engl J Med 1958;259:409-12 78 Stern R, Izant RJ, Boat TF, Wood RE, Matthews LW, Doershuk CF. Treatment and prognosis ofrectal prolapse in cystic fibrosis. Gastroenterology 1986;82:707-10 79 Zemsky WT, Rosenstein BJ. The cause of rectal prolapse in children. Am J Dis Child 1988;142:338-9 80 Siraganian PA, Miller RW, Swender PT. Cystic fibrosis and ileal carcinoma. Lancet 1987;ii:1158 81 Reddington AN, Spring R, Batten JC. Adenocarcinoma of the ileum presenting as non-traumatic clostridial myonecrois in cystic fibrosis. BMJ 1985;200:1871-2 82 Swender PT, Nathan EM, Sondheimer J, Kasowitz MH. Bowel carcioma mimicking mecosin ileus equivalent. Cystic Fibrosis Club -abstracts. Twenty-Third Annual Meeting. Washington, DC. Cystic Fibrosis Club 1982; 23:141 83 Davis TME, Sawicka EH. Adenocarcinoma in cystic fibrosis. Thorax 1985;40:199-200 84 Tedesco FS, Brown R, Schuman BM. Pancreatic carcinoma in a patient with cystic fibrosis. Gastrointest Endowc 1986;32:25-6 85 Roberts JA, Tullett WM, Thomas JStJ, Galloway D, Stack BHR. Bowel adenocarcinoma in a patient with cystic fibrosis. Scott Med J 1986;31:109 86 McKintosh JC, Scho4macher RA, Tiller RE. Pancreatic adenocarcinoma in a patient with cystic fibrosis. Am J Med 1988;85:592 87 Abdul-Karim FW, King TA, Dahms BB, Gauderer MWL, Boat TF. Carcinoma of extrahepatic biliary system in an adult with cystic fibrosis. Gastroenterology 1982;82:758-62 88 Hernanz-Schulman M, Kirkpatrick J, Shwachman H, Herman T, Schulman G, Vawter G. Pneumatosis intestinalis in cystic fibrosis. Radiology 1986;160:497-9
Gastrointestinal complications in cystic fibrosis
J M Littlewood FRCP DCH Regional Cystic Fibrosis Unit, St James' University Hospital, Beckett Street, Leeds LS9 7TF Keywords: gastro-oesophageal reflux; peptic ulcer; Helicobacter pylori, meconium ileus; pancreatitis
The majority of cystic fibrosis (CF) individuals have pancreatic insufficiency which, if not treated, will lead to a variety of gastrointestinal symptoms and signs associated with intestinal malabsorption. With modern pancreatic enzyme replacement therapy, the majority are well controlled. However, a minority have persisting gastrointestinal problems despite large doses of pancreatic enzymes. In some, the malabsorption persists for a variety of reasons which have been reviewed elsewhere'-3. In others there are reasons unrelated to their CF4 5. These alternative or additional explanations should always be considered even when it appears likely that CF is directly responsible for the gastrointestinal symptoms.
Oropharynx Histological abnormalities have been described in the salivary glands and these glands may be enlarged6. These changes have little practical relevance in the pathogenesis of the malabsorption but the secretion of amylase is said to be increased. Lingual lipase may contribute to the apparent slight residual ability to digest fat even in the absence of pancreatic lipase.
Oesophagus Vomiting is a relatively common problem in nonscreened CF infants who present symptomatically and may be the main presenting problem. There is an increased frequency of gastro-oesophageal reflux (GOR) in CF7,8. A recent study identified inappropriate relaxation of the gastro-oesophageal sphincter as the major cause of their reflux9. Severe GOR and associated symptomatic oesophagitis may prove a major problem at any age'0. Symptoms of reflux may be controlled by standard medical treatment including thickening feeds-in CF with cereal to enhance energy intake and a change to more solid food generally. Alkalis and H2 receptor antagonists should be used if there are any signs suggesting oesophagitis. Cisapride is of some value and was effective in controlling the reflux in 8 of 10 CF infants in one study". In the young CF patient with reflux and vomiting sufficient to interfere with weight gain, a fundoplication may be required. In addition to the usual anti-reflux treatment, a more aggressive approach to the chest infection with high doses of intravenous antibiotics may lead to a significant reduction in vomiting and improvement of the oesophagitis. It is our impression that GOR is of clinical significance in a minority of young CF patients but becomes of increasing importance in older patients with more severe chest problems when GOR may result in severe oesophagitis and eventual oesophageal stricture. Patients with GOR had worse lung function
than those with negative barium studies in the experience of one clinic'2.
Stomach No specific histological abnormalities have been described in the stomach. Although delayed gastric emptying has been suggested, a study using epigastric impedance recording, a non-invasive, non-isotopic technique, failed to show prolongation of gastric emptying of clear fluids in CF patients compared with controls and an insignificant difference with low fat
liquids'3. Peptic ulcer is usually a result of severe physical stress rather than a specific problem associated with the CF'4. In one autopsy series of 146 patients, a peptic ulcer was present 12(8%)15. In our CF children and adults peptic ulcer does not appear as a problem. However, although the gastritis due to Helicobacter pylori has been reported to be no more common in 179 CF individuals (11% positive) than 170 controls (16% positive)'6, preliminary results in the Leeds clinic suggest there may be an increased prevalence of Helicobacter pylori in CF (Crabtree J, unpublished observations). The adverse effects of multiple drugs on the gastric mucosa should be considered in patients where vomiting is a problem and gastroscopy may reveal a nonspecific gastritis.
Duodenum and small bowel The small bowel villi are rather taller than normal. Electrical abnormalities of the small bowel mucosa have been described and appear to be related to the basic defect in the epithelial cells17. An enhanced response to amiloride has been observed in the colonic epithelium of CF infants although there is no difference in the resting potential difference; the defect in chloride secretion may be important in the aetiology of distal intestinal obstruction syndrome'8. The duodenal pH is low as reduction in pancreatic bicarbonate secretion is an early and severe feature. The acidic conditions in the upper small bowel lead to bile salt precipitation and defective lipid solubilization19,20. However, although the duodenal and upper jejunal pH is low, most of the small bowel is at a pH 6 or more21 which permits the release of the enzymes from microsphere pancreatin preparations22. The small bowel transit time is prolonged in CF compared to controls21. Meconium ileus Some 10-15% of CF infants present with intestinal obstruction due to meconium ileus (MI3. Of the 386 CF patients referred to Leeds for assessment, 69 (17.9%) had presented with neonatal meconium ileus.
14 Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992
The meconium of CF infants has a decreased water content, electrolytes, except calcium, and proteolytic activity but increased protein. In infants with MI, the ileum and colon contain pellets of inspissated mucous. The calibre of this bowel is small-the unused microcolon. Proximally, the small bowel is dilated and contains thick, sticky meconium. The dilated bowel may undergo volvulus with perforation and peritonitis. Antenatal perforation causes meconium peritonitis with calcification and antenatal volvulus causes ileal atresia, again frequently associated with meconium peritonitis. Although usually associated with CF and pancreatic insufficiency, MI may occur without pancreatic insufflciency24 and in conditions other than CF25. The diagnosis may be suggested by the presence of loops of bowel demonstrating increased echogenicity on ultrasound in the first trimester26 although the reliability ofthis observation has been questioned. In the neonatal period there are symptoms and signs of intestinal obstruction. Loaded loops of bowel may be palpable. The rectum is tight on examination. Abdominal X-ray shows dilated loops of bowel with a ground glass appearance (there is no air in the meconium). Fluid levels are often not demonstrable because of the consistency of the bowel contents. Calcification of intra luminal contents sometimes occurs. Contrast enema usually shows microcolon often with filling defects of the mucous pellets. The differential diagnosis includes Hirschprung's disease, intestinal volvulus, ileal atresia and other surgical emergencies. A significant proportion of infants with MI have peritonitis, volvulus or atresia. A skilled paediatric radiologist can relieve the obstruction with serial gastrografin enemas in
Table 1. Abdominal symptoms and signs in 100 CF patients
Appetite Abdominal pain Fullness Bowels/day Abnormal stools Vomits Distension Palpable mass Liver+spleen
normal 24, good 48, mod 17, small 11 11 (none severe) 9 (2 severe) 1.99 11 4 (occasional in all) 2 4 9 (liver+spleen 5, liver 2, spleen 2)
uncomplicated meconium ileus27. Secure intravenous access, adequate hydration and close monitoring are essential. In case of complications, urgent rsuscitation and surgery may be required so this mode of treatment is only appropriate in a centre with facilities for neonatal surgery. Over -recent years, the outlook for these infants has improved and is similar to that of other CF
infants23MA289. Sequelae of neonatal surgery After the newborn period there may be late complications resulting from loss of resected intestine or the development of stricture or band obstruction at the site of the neonatal anastomosis (Figure 1). Despite the occasional later surgical complications, there is no significant excess of gastrointestinal problems in later childhood and the frequency ofbowel symptoms and nutritional state is similar to those of patients presenting with malabsorption or chest problems (Table 1). CF individuals who have persisting bowel symptomsdespite aeuate pancreatic enzyme therapy should be thoroughly investigated, particularly if they have had neonatal surgery to ensure there is no residual anatomical abnormality.
Dllt intestinal obstruction syndrome (meconium ileus equivalent)_ The distal intestinal obstruction syndrome (DIOS) is characterized by repeated attack of complete or partial intestinal obstruction occurring in a CF individual3s. It has been reported that some 10-47% CF individuals suffer from some degree of recurrent intesti-nal obstruction. It does not appear to be more common in those who presented originally with meconium ileus31. In our clinic 111 of-patients comphlin ofoccasional abdominal pain from any cause and classical DIOS is a rarity (Table 2). In patients with )DIO0, there may be a history of increasing -constipation and inadequate intake of pancteatic supplements suggested by significantly less than average doses or bypoor patient compliance. the presence of a low faecal chymotrypsin in the Table 2. Abdominal pain and palpable mass in 369 CF patients referred to Leeds over the past 11 years T' Presentation
Meconium ileus
16spiatoiy i
.P
II.. ,
i
..
Figure 1. Severe ileal distettion proximal to a stricture atthe site of neonatal intestinal anastomosis after meconium-ieus surgery
Malabsorption S-rin CF sibling
Pain
Mass
26/69 (37.7%) 33/89 (39.0%) 86/184 (47.0%) 1/23 (4.0%) 8/24 (30.0%)
5/69 (7.2%) 5/85 (5.9%) 11/184 (6.0%) 0123 (0.0%) I-
2/24 (8.3%)
Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 15
presence of an apparently reasonable enzyme intake suggests non compliance. Inspissated intestinal contents present in the distal ileum and proximal colon can often be palpated as masses in the right iliac fossa. In some patients there are the classical signs of small bowel obstruction with pain, distension, constipation and bilious vomiting. In CF patients who have DIOS it may be particularly difficult to identify the presence of other conditions such as appendicitis, intussusception, intestinal volvulus, Crohn's disease, small bowel perforation, fistula or ovarian conditions3233.The varying prevalence of the complication supports the view that a chronic under treatment with pancreatic enzymes is important in the development of DIOS3. In Leeds the condition is rare. Intestinal absorption is monitored regularly by dietary assessments and faecal fat estimations and those with significant steatorrhoea (less than 85% absorption of dietary fat intake) have their dose ofpancreatic enzyme increased even if they have no symptoms3. In the few patients who do suffer from recurrent DIOS, compliance- with enzyme taking appears to be a major factor in some but occasionally there is no obvious explanation for their problem. In one series. the diabetes mellitus present in some of the patients and possibly mild dehydration may have been a contributory factor35. Opiate addiction has been implicated as a contributory . factor36. Ultrasound examination may be helpful in identifying the obstructing masses but cannot be relied upon to exclude other causes of pain and obstruction such as intussusception and appendicitis. Investigations should include a serum amylase and erect and supine abdominal radiographs. If the condition is not responding to medical treatment a contrast enema should be performed (see below). Computerised tomography has been recommended to reduce the likelihood of unnecessary surgery and to monitor the treatment of the condition37. Patients with more resistant and prolonged symptoms may be unwell and dehydrated and requiLre urgent intravenous rehydration and exclusion ofother surgical conditions. For patients with mild symptoms of colicky pain and perhaps with a mass, one or more doses of oral gastrografin (diatrizoate) with fluid usually relieves the situation in hours"34. We use the recommended doses of 100 ml of gastrografmi in 400 ml of water or fruit juice for patients over 8 years and 50 ml gastrografin and 200 ml fluid for younger patients; then half dose can- be given daily until clear. Gastrografin can be used as an enema using 100 ml up to three times daily. It is important to maintain adequate hydration. Some prefer to use oral N-acetyl cysteine using a solution of 10-20 g in 100 ml and giving 10 ml three times. daily or-a an- enema uaing 50 ml of the solution with 50 ml of water.. Acute hypomagnesaemia. has been described as a complication of treatment38. An increasingly -popular treatment is the oral administration of large volumes of a balanced electrolyte intestinal lavage. solution39-4l. We have found Klean-Prep a convenient ready mixed preparation. Adults may drink the solution but -children usually require a nasoga tube to .aqhieve. the 20-30 ml/kg body weight per hour required(max-one litre/hour). Usually 2-3 litres of the solution are required for a child and 5-6 litres .for an adult.
Although-the reported overall benefits ofcisapride in CF42 have not been confirmed in a small controlled trial43, the drug may help those with persisting recurrent-episodes of DIOS and/or constipation41. The incidence of DIOS does not appear to have increased following relaxation of fat restriction after the introduction of acid resistant pancreatic supple.ments. Compliance with taking pancreatic enzymes is a major problem particularly in older patientsthis at a time when growth results in a relative decrease in the number of enzyme capsules per kilogram of body weight". Thus, a check on the adequacy of and compliance with pancreatic replacement therapy should follow an acute episode of DIOS. Regular doses of oral gastrografm (perhaps every weekend) have proved effective in some patients with more chronic low grade symptoms which persist even after improving intestinal absorption.
Constipation and acquired megacolon Although many CF patients have abdominal pain due to DIOS some patients have primarily an acquired megacolon syndrome with chronic faeeal retention45; there is not necessarily 'the passage of hard and infrequent stools'. There may be either reduced bowel frequency and occasionally severe overloading.even resulting in soiling. Distal colonic obstruction severe enough to require laparotomy has been described46. There is usually impressive evidence of colonic faecal overloading on the abdominal radiograph. These patients have often been diagnosed late or received inadequate treatment with pancreatic enzymes resulting in chronic faecal accumulation. If such patients are suddenly given increased doses of pancreatic enzymes to control the chronic malabsorption which most of them have, they .may develop severe constipation which requires vigorous laxative treatment similar to that used for DIOS-which may also be present. Treatment, in non-acute cases, is first to ensure that absorption is adequately controlled by gradually increasing the pancreatic enzyme supplement until the faecal fat absorption is reasonable (more than 85%) and also treat with laxatives-either regular lactulose, Senokot (senna), gastrografin (diatrizoate) or even balanced electrolyte intestinal lavage solution. Abdominal radiograph to determine the degree of faecal overloading is a helpful addition to history and examination not only in diagnosis but also in determining effectiveness of the treatment. Cisapride has proved helpful in some of these patients4l, as it is in non CF individuals who have severe constipation47.
Appendicitis In -a recent review of 1220 CF patients, a total of 60 (4.9%) patients had undergone appendicectomy. The authors ooncluded that the spectrum of appendiceal disease, in CF varied from simple mucus distention to classical acute appendiiis with perforation. Pain from a non-in"flamed distended appendix represented a distinct syndrome in (CF patients". In a review of five cases of appendicitis, the high incidence of abcess formation in CF patit was noted altfhough the incidence of appendicitis as such was relatively low in CF individuals. In 49 of 51 autopsied CF patients the mueosa -was hyperplastic, and the glands distended with eoainophilic material49.'In a recent report of nine patients.from the Toronto clinic,
16 Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992
eight had abscesses and in four operation was delayed for more than 3 days50. Appendicitis should be considered in any CF patient with suggestive symptoms particularly if the barium enema shows extrinsic compression of the caecum. Ultrasound, CT and gallium scans are of limited value3350. Even with present day investigations, abdominal tenderness remains one of the most important signs of abscess51. Intussusception of the appendix has been described and is an alternative explanation for cramping lower abdominal pain in the CF patients52.
Intussusception Intussusception has been mentioned already but it should be emphasized that the condition should always be suspected in any patient with colicky abdominal pain even if previously affected distal ileal obstruction syndrome. It has been estimated that 1% of CF patients have intussusception, but this report was before microsphere preparations were available53. The main clinical features were colicky abdominal pain (77%), a palpable mass (68%), vomiting (57%) and rectal bleeding (23%). Not all would agree that ultrasound is 'a reliable non-invasive method to confirm or exclude intussusception'54 despite the characteristic bull's eye appearance55. In our experience abdominal ultrasound may miss intussusception in CF patients and a contrast enema should be an early investigation and will usually suggest the diagnosis56. The intussusception may be chronic in CF patients as in one case reported54. A suggested approach to the management of a CF patient with severe colicky pain and a right iliac fossa mass has been proposed by Smith et al.33 An initial contrast enema should be performed to exclude intussusception and may also be therapeutic. If not effective, balanced electrolyte intestinal lavage solution therapy should be used, proceeding if necessary to an ultrasound and/or CT scan followed by repeat lavage. Finally laparotomy should be considered. We would support the importance of a contrast enema at early stage in an attempt to rule out intussusception. We have also failed to identify intussusception by ultrasound examination. Increasing local tenderness and the patient's general condition are also of paramount importance in deciding on the need for surgical intervention. Pancreatitis Histological abnormalities of the pancreas are present in all CF infants at birth57. In the majority of patients there is reduced secretion of both pancreatic enzymes and bicarbonate. A minority of CF patients (between 5 and 15% depending on the clinic) do not have steatorrhoea as there is sufficient pancreatic function to control intestinal absorption58. A very occasional CF patient has pancreatic calcification which does not appear to have a particular clinical association59. There have been two examples of pancreatic calcification in the 386 patients
referred
to Leeds.
Pancreatitis is a well described complication in older CF patients who have some residual pancreatic function60 61. Cystic fibrosis should be considered in all patients with acute or relapsing pancreatitis even if there are no other features suggesting the diagnosis. Pancreatic serum enzymes, usually low in CF, are raised in the patients who have pancreatitis. Pancreatic ultrasound, usually abnormal by mid
childhood, but may be normal in pancreatic sufficient
patients"4. Cows' milk intolerance Vomiting, failure to thrive or persisting bowel problems may be due to cows' milk intolerance (CMI). The symptom triad of hypoproteinaemia, oedema and anaemia has been attributed to CMI63. More recently CMI has been proved by serial jejunal biopsies in CF infants and it is important to consider this possibility in any CF infant who is failing to thrive"'. The resolution of diarrhoea and improved absorption observed in some CF infants following a change to a cows' milk free formula such as Pregestimil may be related to CMI. However, clinical food allergy and intolerance is unusual in older CF patients even though many are atopic; it has been suggested that antigen absorption may be impaired in CF as evidenced by the fewer than expected positive RASTs to foods65. Coeliac disease Coeliac disease is well documented as occurring in CF patients66'67 and appears to be more common than in the general population. Recently five CF patients with coeliac disease have been reported in a CF population of 1100 (1 in 220). Coeliac disease was diagnosed in these patients following investigation of persisting clinical and biochemical evidence of malabsorption despite apparently adequate pancreatic supplements. All had subtotal villous atrophy of the jejunal mucosa which responded to a gluten free diet and histological relapse after subsequent gluten challenge68. Although gliadin antibodies may prove of value in identifying CF individuals at risk for coeliac disease, their reliability has not been evaluated in CF. Therefore a jejunal biopsy should be included in the investigations of any CF patient who has persisting bowel symptoms and malabsorption despite apparently adequate pancreatic enzyme treatment.
Giardiasis In one USA series of CF patients an impressive number were infected with Lamblia giardia. A cross sectional study, using a sensitive ELISA method for identification, showed that 28% of CF patients were positive for giardia compared to 6% of controls69. Although we have diligently searched for giardiasis in many CF patients with persisting bowel problems, admittedly not using a sensitive ELISA test, we have failed to identify the protozoan as a significant problem in our CF patients. However, there have been isolated reports of giardiasis affecting CF patients in this country4. Crohn's disease Crohn's disease in CF patients has been reported on a number of occasions and can prove difficult to diagnose before laparotomy, which may itself be delayed, the symptoms being attributed to DIOS. Before the mid 80s, when the acid resistant pancreatic preparations became generally available in the UK, it is likely that all but the most florid examples of Crohn's disease were attributed to the malabsorption, unless the diagnosis had been made at laparotomy. The increasing frequency of reports of Crohn's disease in CF patients may be related to their increased survival70-74. It has been suggested that inflammatory bowel disease is more likely to develop after meconium
Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 17
ileus75 and the increased survival of these infants may be relevant76. Also the improved recognition of Crohn's disease in children and adolescents by the availability and more frequent resort to fibreoptic endoscopy may have permitted more accurate histological diagnosis in some cases. It is sound advice that 'any patient with CF who does not have an obvious explanation for failure to thrive or growth failure as a result of advanced pulmonary disease or who fails to respond to treatment for pancreatic insufficiency needs a full work-up that includes demonstration of the anatomical status of the intestinal tract'74 75. One would stress that the investigations would include biopsies of the gastric, duodenal and colonic mucosae for histology. There has been no CF patient recognized as having Crohn's disease in over 400 CF patients known to the Leeds clinic. Rectal prolapse There is a definite but variable association with rectal prolapse recognized for many years in the untreated CF patient77. Rectal prolapse occurred in 18.5% of one series of CF patients, usually in the second or third years and commonly before adequate pancreatic replacement therapy was started78. The complication is rare after the age of 5 years. In patients referred to Leeds, 57/386 (14.8%) had experienced at least one episode ofrectal prolapse. The frequency varied with the mode of presentation being 11.5% (10/69) in those presenting with meconium ileus, 20.1% (37/184) in those presenting with gastrointestinal signs and 11.8% (10/85) in those presenting with respiratory symptoms. Further prolapse is usually prevented by control of the malabsorption and improved nutrition following the start of treatment. In a recent series of children presenting with rectal prolapse only six (11%) had cystic fibrosis79. Nevertheless a sweat test should be performed in any children with this problem. Intra abdominal malignancy As the survival of CF individuals improves, there have been a number of reports of malignant disease. Adenocarcinoma of the ileum has been reported in four patients80. Another presented as clostridial myonecrosis81. Bowel carcinoma may mimic meconium ileus equivalent82'83. Carcinoma84 and adenocarcinoma85'88 of the pancreas have been described and carcinoma of the extrahepatic biliary system87. The increasing frequency of these reports have been advanced as a reason for routine CF postmortem examinations. Pneumatosis intestinalis Intramural gas is described in CF patients with severe pulmonary disease. The condition was found in 41 of 491 patients coming to autopsy in Boston88. We have no experience of the condition in over 400 CF patients. Twenty-four died but few have a postmortem
examination. Conclusion Abdominal symptoms and signs are infrequent in those patients whose intestinal absorption is well controlled. The CF patient may, of course, suffer from any of the intra-abdominal conditions which occur in the non-CF individual. It is important that these are considered both as the main cause of the patient's
Table 3. Investigation ofpersisting abdominal symptoms
Review diet, faecal fat and percentage absorption Check enzyme therapy and faecal chymotrypsin Consider whether medication causing symptoms Urinalysis (renal ultrasound if urine abnormal) Full blood count, erythrocyte sedimentation rate or plasma viscosity Urea, electrolytes, amylase, liver function tests Helicobacter pylori antibodies Abdominal radiograph for faecal loading Check for gut infection and giardiasis Hydrogen breath test for small bowel infection Ultrasound gallbladder, bile ducts and pancreas Radiograph contrast studies to check gut anatomy Exclude coeliac disease and food intolerance Gastroscopy, colonoscopy with biopsies Consider emotional factors Surgical opinion ? laparotomy
symptoms and also as an additional complication of an existing CF-related disorder, eg appendicitis or intussusception in a patient who already has distal ileal obstruction. The improved longevity of patients and the better control of their malabsorption, and its associated symptoms, have permitted more frequent recognition of gastrointestinal complications and additional disorders. A CF patient with persisting abdominal symptoms and signs, despite adequate doses of pancreatic enzymes, deserves full gastrointestinal investigation (Table 3) to exclude the other disorders which are unrelated to the CF yet amenable to appropriate treatment. Acknowledgments: The author thanks Mr John Beck for sharing his great experience in managing infants with meconium ileus and Dr Steve Conway for helpful discussion and suggestions. References 1 Park RW, Grand RJ. Gastrointestinal manifestation of cystic fibrosis: a review. Gastroenterology 1981;81:1143-61 2 Durie PR, Pencharz PB. A rational approach to the nutritional care of patients with cystic fibrosis. J R Soc Med 1989;82(suppl 16):11-20 3 Littlewood JM. Pancreatic enzymes in cystic fibrosis. In: Lankisch PG, ed. Pancreatic enzymes in health and disease. Berlin: Springer-Verlag, 1991:177-89 4 Baxter PS, Dickson JA, Variend S, Taylor CJ. Intestinal disease in cystic fibrosis. Arch Dis Child 1988;63:1496-7 5 Dalzell AM, Heaf DP, Carty H. Pathology mimicking distal ileal obstruction syndrome in cystic fibrosis. Arch Dis Child 1990;66:540-1 6 Barbero GJ, Sibinga MS. Enlargement of submaxillary salivary gland in cystic fibrosis. Pediatrics 1962;29: 788-93 7 Bendig DW, Wagner ML, Harrison GM, et al. Complications of gastroesophageal reflux in cystic fibrosis. J Pediatr 1982;100:536-40 8 Scott RB, O'Laughlin EV, Gall DG. Gastroesophageal reflux in patients with cystic fibrosis. J Pediatr 1985;106:223-7 9 Cucchiara S, Santamaria F, Andreotti MR, et al. Mechanisms of gastro-oesophageal reflux in cystic fibrosis. Arch Dis Child 1991;66:617-22 10 Feigelson J, Girault F, Pecau Y. Gastroesophageal reflux and esophagitis in cystic fibrosis. Acta Paediatr Scand 1987;76:989-90
18 Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992
11 Dab I, Malfoot A. Gastro-oesophageal reflux: a primary defect in cystic fibrosis. Scand J Gastroenterol Suppl 1988;143:125-31 12 Stringer DA, Sprigg A, Joudis E, et aL The association of cystic fibrosis, gastroesophageal reflux, and reduced pulmonary function. Can Assoc Radiol J 1988;39: 100-2 13 Smith HL, Hollins GW, Booth IW, Weller PH. Gastric emptying of liquids in cystic fibrosis. 16th European working group for cystic fibrosis. Prague, 1989: 83 14 Aterman K. Duodenal ulceration and fibrocystic disease of the pancreas. Am J Dis Child 1961;101:210 15 Oppenheimer EH, Esterley JR. Pathology of cystic fibrosis. Review of the literature and comparison with 146 autopsied cases. Perspect Pediatr Pathol 1975;2:241-78 16 Przyklenk B, Bauerfeind A, Bertele-Harms RM, Harms KH. The significance of Helicobacter pylori in patients with cystic fibrosis. 17th European cystic fibrosis conference. Copenhagen. 1991. Poster No 72:85 17 Baxter PS, Wilson AJ, Read NW, Hardcastle J, Hardcastle PT, Taylor CJ. Abnormal jejunal potential difference in cystic fibrosis. Lancet 1989;i:464-6 18 Gowen CW, Gowen MA, Knowles MR. Colonic transepithelial potential difference in infants with cystic fibrosis. J Pediatr 1991;118:412-15 19 Zentler-Munro PL, Fitpatrick WJF, Batten JC, Northfield TC. Effect of intrajejunal acidity on aqueous phase bile acid and lipid concentration in pancreatic steatorrhoea due to cystic fibrosis. Gut 1984;25.:500-7 20 Zentler-Munro PL. Pancreatic insufficiency and cystic fibrosis. Curr Opin Gastroenterol 1989;5:706-10 21 Gilbert J, Kelleher J, Littlewood JM, Evans DF. Ileal pH in cystic fibrosis. Scand J Gastroenterol 1988; 23(suppl 1):132-4 22 Littlewood JM, Kelleher J, Walters MP, Johnson AW. In vivo and in vitro studies of microsphere pancreatic supplements. J Pediatr Gastroenterol Nutr 1988;7 (suppl 1):S22-S29 23 Rescorla FJ, Grosfeld JL, West KJ, Vane DW. Changing pattern of treatment and survival of neonates with meconium ileus. Arch Surg 1989;51:34-48 24 Lands L, Zinman P, Wise M, Kopelman H. Pancreatic function testing or meconium ileus in cystic fibrosis: two case reports. JPediatr Gastroenterol Nutr 1988;7:276-9 25 Noblett H. Meconium ileus. In: Ravitch M, Welsh K, Benson C, et aL eds. Pediatric surgery. Chicago: Year Book Medical, 1979: 943 26 Benacerraf BR, Chaudhury AK. Echogenic fetal bowel in the third trimester aated with- meconium ileus secondary to cystic fibrosis. A case report. JReprod Med 1989;34:299-300 27 Noblett HR. Treatment of uncomplicated meconium ileus by gastrografin enema: a preliminary report. J Pediatr Surg 1969;4:190-7 28 Caniano DA, Beaver BL. Meconium ileus: a fifteen-year experience with forty-two neonates. Surgery 1987; 102:699-703 29 Dinwiddie R, Spitz L, Kiely E. Current management ot meconium ileus. 16th European working group for cystic fibrosis. Prague, 1989: 89 30 Jensen KG. Meconium ileus equivalent in a 15 year old patient with mucoviscidosis. Acta Pediatr Scand 1962; 51:344-8 31 Rosenstein BJ, Longbaum TS. Incidence of distal intestinal obstruction syndrome in cystic fibrosis. J Pediatr Gastroenterol Nutr 1983;2:299-301 32 Weller PH, Wiliams J. Clinical features, pathogenesis and management of mecomum ileus equivalent. JR Soc Med 1986;79(suppl 12):36-7 33 Smith HLL, Weller PH, Gornall P, Chapman 5, Jones TJ. Pitfalls in the diagnosis of appendix abscess in cystic fibrosis. J R Soc Med 1989;829(suppl 16):564-6 34 O'Halloran SM, Gilbert J, McKendrick DM, Cart HML, Heaf D. Gastrografin in acute meconium ileus equivalent. Arch Dis Child 1986;61:1128-30 35 Hodson ME, Mearns MB, Batten JC. Meconium ileus
equivalent in adults with cystic fibrosis. BMJ 1976; ii:790-1 36 Koletzko S, Stringer DA, Cleghorn GJ, Durie PR. Lavage treatment of distal intestinal obstruction syndrome in children with cystic fibrosis. Pediatrics
1989;83:727-33 37 Moody AR, Haddock JA, Given-Wilson R, Adam EJ. CT monitoring of therapy for meconium ileus. JComputer Assisted Tomography 1990;14:1010-12 38 Godson C, Ryan MP, Brady HR, Bourke S. Acute hypomagnesaemia complicating the treatment of meconium ileus equivalent in cystic fibrosis. Scand JGasroenterol Suppi 1988;143:140-50 39 Cleghorn GJ, Forstuer GG, Stringer PA,-Durie PR. Treatment of distal intestinal obstructionsyndrome in cystic fibirsis with a balanced intestinal lavage solution. Lancet 1986;i:8-11 40 Davidson AC, Harrison K, Steinfort CL, Geddes DM. Distal intestinal obstruction in cystic fibrosis treated by oral intestinal lavage, and a case of recurrent obstruction despite normal pancreatic function. Thorax 1987;42:538-41 41 Koletzko S, Corey M, Ellis L, Spino M, Stringer DA, Durie PR. Effects of cisapride in patients witlx cystic fibrosis and distal intestinal obstruction. J Pediatr
1990;117-:815-22 42 Prinsen JE, Thomas M. Cisapride in cystic fibrosis. Lancet 1985;i:512-13 43 Smith HL, Handy DJ, Weller PH, Booth IW, Cisapride and cystic fibrosis. Lancet 1989;i:338 44 Andersen HD, Hjelt K, Waever- E, Overgaard K. The age-related incidence of meconium ileus equivalent in a cystic fibrosis population: the impact of high energy intake. J Pediatr Gastroenterol Nutr 1990;11:356-60 45 Rubinstein S, Moss R, Lewiston N. Constipation and meconium ileus equivalent in patients with cystic fibrosis. Pediatrics 1986;78:473-9 46 Apelgmen KN, Yuen JC, Distal colonic impaction requiring laparotomy in an adult with cystic fibrosis. J Clin Gastroenterol 1989;11:687-90 47 Murray RD, Ulysses B, Li K. Juhling McClung H, Heitlinger L, Rehm D. Cisapride for intractable constipation in children: observations from an open trial. J Pediatr Gastroenterol Nutr 1990;11:503-8 48 Coughlin JP, Gauderer MW, Stern RC, Doershuik CF, Izant RJ, Zollinger RM. The spectrum of appendiceal disease in cystic fibrosis. JPediatr-Surg 1990;2:835-9 49 McCarthy VP, Mischler EH, Chernick MS, Di Sant'Agnese P. Appendiceal abscess in cystic fibrosis. Gastroenterology 1984;86:564-8 50 Shields MD, Levison H, Ris8man JJ, Durie PR, Canny GJ. Appendicitis in cystic fibrosis. Arch Dis child
1990;-6:307-10 51 Dobrin PB, HeerGully P, Greenlee HB, et aL Radiologic diagnosis of intraabdominal abscess. Do multiple tests help? Arch Surg 1986;121:41-6 *52 McKintosh JC, Mroczek EC, Baldwin C, Mestre J. Intussusception of the appendix in a patient with cyatic fibrosis. J Pediatr Gastroenterol Nutr 1990;11:542-4 53 Holsclaw D, Rocmans C, Shwachman H. Intuasusception in patients with cystic fibrosis. Pediatrics 1971;48:51-8 54 Webb-AK, Khan A. Chronic intussusception in a young adult with cystic fibrosis.- J R- Soc Med 1989;8a(suppl
16):47-8 55 Mulvihill DM. Ultrasound findings of chronic intussuseption in a patient with cystic fibrosis. J Ultrasound Med 1988;7:353-5 56 Holmes M, Murphy V, Taylor M, Denham B. Intussusoption in cystic fiboi. ArhDis Child 1991;#6:726-7 57 Imnie J, Fagan D, Sturgess J. Quantitative evaluation of the-development of the exocrine pancreas in'CF and control infants. Am J Pathol 1979;9B5:697-707 58 D)ure PR, Forstner GG. Pathophysiology of the exocrine pancreas in cystic fibrosis. JR Soc Med 1989;82suppl
i6):2-10
Journal of the Royal Society of Medicine Supplement No. 19 Volume 85 1992 19 59 Liu P, Daneman A, Stringer D, Durie PR. Pancreatic cysts and calcification in cystic fibrosis. J Can Assoc Radiol 1986;37:279-81 60 Shwachman H, Lebenthal E, Khaw K. Recurrent acute pancreatitis in patients with cystic fibrosis with normal pancreatic enzymes. Pediatrics 1975;55:86-94 61 Gross V, Schoelnerich J, Denzel K, Gerok W. Relapsing pancreatitis as initial manifestation of cystic fibrosis in a young man with cystic fibrosis. Int J Pancreatology 1989;4:21-228 62 Wilson-Sharp RC, Irving HC, Brown RC, Chalmers DM, Littlewood JM. Ultrasonography of the pancreas, liver, and biliary system in cystic fibrosis. Arch Dis Child 1984;59:923-6 63 Skopnik H, Heinman G. Manifestation of intolerance to cow's milk protein in mucoviscidosis with the symptom triad of hypoproteinaemia, edema and anaemia. Klin Padiabr 1987;199:453-6 64 Hill SM, Phillips AD, Mearns M, Walker-Smith JA. Cow's milk sensitive enteropathy in cystic fibrosis. Arch Dis Child 1989;64:1251-5 65 Ferguson A, Merrett TG, Littlewood JM, Bolderson I. IgE antibodies to foods are not a feature of cystic fibrosis. Hum Nutr:Clin Nutr 1986;40C:255-8 66 Goodchild MC, Nelson R, Anderson CM. Cysticfibrosis and coeliac disease: coexistence in two children. Arch Dis Child 1973;48:684-91 67 Taylor B, Sokel G. Cystic fibrosis and coeliac disease. Arch Dis Child 1973;4*:692-6 68 Valletta EA, Mastella G. Incidence of coeliac disease in a cystic fibrosis population. Acta Paediatr Scand 1989;78:784-5 69 Roberts DM, Craft JO, Mather FJ, Davis SH, Wright JA. Prevalence of giardiasis in patients with cystic fibrosis, J Pediatr 1988;112:555-9 70 O'Connor J, Lawson J. Fibrocystic disease of the pancreas and Crohn's disease. BMJ 1972;4:610 71 Euler AR, Ament ME. Crohn's disease-a cause of arthritis, oxalate stones and fistulae in cystic fibrosis. West Med J 1976;125:315-17 72 Ojeda VJ, Levitt S, Ryan G, Laurence BH. Cystic fibrosis. Crohn's colitis and adult meconium ileus equivalent. Dis Colon Rectum 1986;29:567-71 73 Behrens R, Segerer B, Bowing B, Bender SW. Crohn's disease in cystic fibrosis. J Pediatr Gastroenterol Nutr
1989;9:528-31
74 Lerner A, Gal N, Mares AJ, Maor E, Iancu TC. Pitfall in the diaguosis of Crohn's disease in a cystic fibrosis pAtioi. J PI4diatr Gtroenterol Ntsfr 1990;12:369-71 75 Lloyd-Still JD. Cystic fibrosis, Crohn's disease, biliary abnormalities, and cancer. JPediatr Gastroenterol Nutr 1990;11:434-7 76 Maboguje OA, Goldthorn JF, Wang CI, Hossein Mahour G. Colonic polyps and coloduodenal fistula: unusual complications in a patient with cystic fibrosis. Surgery 1981;90:114-16 77 Kulczycki LL, Shwachman H. Studies in cystic fibrosis of the pancreas: occurrence of rectal prolapse. N Engl J Med 1958;259:409-12 78 Stern R, Izant RJ, Boat TF, Wood RE, Matthews LW, Doershuk CF. Treatment and prognosis ofrectal prolapse in cystic fibrosis. Gastroenterology 1986;82:707-10 79 Zemsky WT, Rosenstein BJ. The cause of rectal prolapse in children. Am J Dis Child 1988;142:338-9 80 Siraganian PA, Miller RW, Swender PT. Cystic fibrosis and ileal carcinoma. Lancet 1987;ii:1158 81 Reddington AN, Spring R, Batten JC. Adenocarcinoma of the ileum presenting as non-traumatic clostridial myonecrois in cystic fibrosis. BMJ 1985;200:1871-2 82 Swender PT, Nathan EM, Sondheimer J, Kasowitz MH. Bowel carcioma mimicking mecosin ileus equivalent. Cystic Fibrosis Club -abstracts. Twenty-Third Annual Meeting. Washington, DC. Cystic Fibrosis Club 1982; 23:141 83 Davis TME, Sawicka EH. Adenocarcinoma in cystic fibrosis. Thorax 1985;40:199-200 84 Tedesco FS, Brown R, Schuman BM. Pancreatic carcinoma in a patient with cystic fibrosis. Gastrointest Endowc 1986;32:25-6 85 Roberts JA, Tullett WM, Thomas JStJ, Galloway D, Stack BHR. Bowel adenocarcinoma in a patient with cystic fibrosis. Scott Med J 1986;31:109 86 McKintosh JC, Scho4macher RA, Tiller RE. Pancreatic adenocarcinoma in a patient with cystic fibrosis. Am J Med 1988;85:592 87 Abdul-Karim FW, King TA, Dahms BB, Gauderer MWL, Boat TF. Carcinoma of extrahepatic biliary system in an adult with cystic fibrosis. Gastroenterology 1982;82:758-62 88 Hernanz-Schulman M, Kirkpatrick J, Shwachman H, Herman T, Schulman G, Vawter G. Pneumatosis intestinalis in cystic fibrosis. Radiology 1986;160:497-9
