British UttBcal Bulletin (1992) \W 48, No 4, pp»47-8» O The Bntnh Councfl 1992

Gastrointestinal complications J M Littlewood Regional Cystic Fibmsts Unit, St James University Hospital, Leeds, UK

An individual who has cystic fibrosis (CF) may suffer from gastrointestinal problems related to inadequately controlled intestinal absorption secondary to the pancreatic insufficiency. These include neonatal meconium ileus, distal intestinal obstruction syndrome (DIOS), constipation and acquired megacolon, rectal prolapse and rarely pancreatitis. If the intestinal malabsorption is well controlled with an effective pancreatic enzyme preparation, DIOS, constipation and rectal prolapse are infrequent. Persisting gastrointestinal symptoms should be investigated thoroughly to exclude other disorders not directly related to the cystic fibrosis; these include cows' milk intolerance, coeliac disease, giardiasis, Crohn's disease and intra-abdominal malignancy. Both appendicitis and intussusception may cause difficult diagnostic problems particularly in patients who may also have distal ileal obstruction syndrome.

Individuals who have cystic fibrosis (CF) may develop a variety of gastrointestinal disorders. Some of these are related, to a greater or lesser extent, to the pathophysiological changes associated with the CF but they are also subject to the many gastrointestinal conditions which may affect individuals who do not have cystic fibrosis. The frequency of gastrointestinal problems clearly associated with the CF (eg distal intestinal obstruction) appears to be related to the efficiency of the pancreatic enzyme replacement therapy to control the intestinal malabsorption.1*2 Cystic fibrosis individuals take many oral treatments and these should be remembered when seeking an explanation for a gastrointestinal upset.

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STOMACH AND OESOPHAGUS Vomiting is a relatively common problem in CF infants and may be the main mode of presentation. The increased frequency of gastro-oesophageal reflux (GOR) in CF individuals is well documented.3-5 Severe GOR and associated symptomatic oesophagitis may prove a major problem at any age.6 Inappropriate relaxation of the gastro-oesophageal sphincter has been implicated as the major cause of the GOR.7 Prolonged intra oesophageal pH recordings in young CF infants have confirmed the high prevalence of GOR and lend further support to the view that the condition may have a deleterious effect on respiratory function. It has been shown that the motility promoting drug cisapride may have an impressive beneficial effect (uncontrolled study) on the GOR and respiratory function.8 Symptoms of reflux may be controlled by standard medical treatment of posture, thickening feeds, whilst alkalis and H2 blockers should be used if there are any signs suggesting oesophagitis. Cisapride is of some value8 and was effective in controlling the reflux in 8 of 10 CF infants in one study.9 Rarely a fundoplication operation may be required; the presence of CF should not be a deterrent if surgery is indicated. A more aggressive approach to the chest infection with high dose intravenous antibiotic treatment may lead to a significant reduction in vomiting and improvement of the oesophagitis. Peptic ulcer is usually the result of severe physical stress rather than a specific problem associated with the cystic fibrosis16 and present in 8% of one autopsied series.11 In our CF children and adults there is no increased prevalence of peptic ulcer. However, although the gastritis due to Helicobacter pylori has been reported to be no more common in 279 CF individuals (11% positive) than 170 controls (16% positive),12 our preliminary experience suggests there may be an increased prevalence of Helicobacter pylori in CF patients. The infection should be excluded in those patients with persisting upper gastrointestinal symptoms either by serology or endoscopy. The gastroscopy may also reveal nonspecific gastritis due to medications.

DUODENUM AND SMALL BOWEL The duodenal pH is low as reduction in pancreatic bicarbonate secretion is an early and cardinal feature. The acidic conditions in the upper small bowel lead to bile salt precipitation and defective lipid solubilisation13 {see Durie and Pencharz, this issue). However, most of the small bowel is at a pH 6 or more14 permitting the release of the enzymes from microsphere pancreatic preparations.15

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MECONIUM ILEUS Of the 386 CF patients referred to Leeds for assessment, 69 (17.9%) had presented with neonatal meconium ileus (MI) which is comparable with the usually reported 10 to 15%. Over recent years, the outlook for these infants has improved and is similar to that of other CF infants.16 Infants with MI have pellets of inspissated mucus in the ileum and colon. The calibre of the distal 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. Meconium ileus may occur without pancreatic insufficiency17 and in conditions other than CF.18 The diagnosis may be suggested by the presence of loops of bowel demonstrating increased echogenicity on ultrasound in the first trimester19 although the reliability of this 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 mucus 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 uncomplicated meconium ileus.20 Secure intravenous access, adequate hydration and close monitoring are essential in a centre with facilities for neonatal surgery. 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; thus persisting bowel symptoms despite adequate pancreatic enzyme therapy should be thoroughly investigated in any CF patient, particularly if the patient had neonatal surgery. DISTAL INTESTINAL OBSTRUCTION SYNDROME (MECONIUM ILEUS EQUIVALENT) The distal intestinal obstruction syndrome (DIOS) is characterised by repeated attacks of complete or partial intestinal obstruction occurring

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in a CF individual21 and affects between 10 and 47% of CF individuals. In our clinic 11 % of patients complain of occasional abdominal pain from any cause and classical DIOS is a rarity. This low prevalence may be due to periodic monitoring of intestinal absorption and increasing the dose of pancreatic enzymes to control chemical steatorrhoea rather than merely adjusting the dose to control the symptoms of malabsorption. Our experience supports the suggestion that inadequate doses of pancreatic enzymes are important in the aetiology of DIOS.2 There may be a history of inadequate intake of pancreatic supplements suggested by a dose significantly less than average or by suspected or known poor patient compliance. Growth of the patient often results in a relative decrease in the number of enzyme capsules per kilogram of body weight.23 Opiate addiction has been implicated as a contributory factor.24 Inspissated intestinal contents 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 which should always be considered as alternative explanations; these include appendicitis, intussusception, intestinal volvulus, Crohn's disease, small bowel perforation, fistula, neoplasm or ovarian conditions.25 Ultrasound 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 x-rays. If the condition is not responding to medical treatment a contrast enema should be performed (v. infra). CT has been recommended to reduce the likelihood of unnecessary surgery and to monitor the treatment of the condition.26 Patients with more resistant and prolonged symptoms may be unwell and dehydrated and require urgent intravenous rehydration and exclusion of other surgical conditions. For patients with mild symptoms of colicky pain perhaps with a mass, one or more doses of oral gastrografin (diatrizoate) with fluid usually relieves the situation in hours.27 100ml of gastrografin in 400ml of water or fruit juice for patients over 8 years and 50ml gastrografin and 200ml fluid for younger patients; then half doses can be given daily until clear. Gastrografin can be used as an enema using 100ml up to three times daily. It is important to maintain adequate hydration if necessary by the intravenous route. Some prefer to use oral N-acetyl cysteine using a solution of 10-20g in 100ml and giving 10ml three times daily or as an enema using 50ml of the solution

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with 50ml of water. Acute hypomagnesaemia has been described as a complication of such treatment 28 An increasingly popular treatment is the oral administration of large volumes of a balanced electrolyte intestinal lavage solution.24-29 Adults may drink the solution but children usually require a nasogastric tube to achieve the 20-30ml/kg body weight per hour required (maximum 1 1/h). Usually 2-3 1 of the solution are required for a child and 5—6 1 for an adult (see Figs 1 and 2). Thus, a check on the adequacy of and compliance with pancreatic replacement therapy should follow an acute episode of DIOS. Regular doses of oral gastrografin (perhaps every weekend) have proved effective in some patients with more chronic low grade symptoms which persist even after improving intestinal absorption. Regular cisapride is useful in those with recurrent episodes of DIOS and/or constipation.30 Children are given 0.2mg/kg/dose three times daily and increased if necessary until the adult dose of lOmg three times daily is reached. CONSTIPATION AND ACQUIRED MEGACOLON Although many CF patients have abdominal pain due to DIOS some patients have primarily an acquired megacolon syndrome with chronic faecal retention.31 There may be either reduced bowel frequency and occasionally extending to severe rectal overloading even resulting in incontinence. Distal colonic obstruction severe enough to require laporotomy has been described.32 There is usually impressive evidence of colonic faecal overloading on the abdominal x-ray which is a very useful investigation both in confirming the presence of colonic overloading and in determining the effect of treatment 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 (ie more than 85% of the intake). Then laxative treatment is usually required—either regular lactulose, Senokot (senna), gastrografin (diatrizoate) or even balanced electrolyte intestinal lavage solution. Cisapride has proved helpful in some of these patients,30 as it is in non CF individuals who have severe constipation.33

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Fig. 1 Severe constipation before balanced electrolyte intestinal lavage solution.

APPENDICITIS In a recent review of 1220 CF patients, a total of 60 (4.9%) patients had undergone appendectomy. The authors concluded that the spectrum of appendiceal disease in CF varied from simple mucus distention to

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Fig. 2 Complete clearance after balanced electrolyte intestinal lavage solution.

classical acute appendicitis with perforation. Pain from a non-inflamed distended appendix represented a distinct syndrome in CF patients.34 In a review of 5 cases of appendicitis, the high incidence of abscess formation in CF patients was noted although the incidence of appendicitis as such was relatively low in CF individuals. In 49 of 51 autopsied CF patients the mucosa was hyperplastic, and the glands distended with

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eosinophilic material.35 In a recent report of 9 patients from the Toronto clinic, 8 had abscesses and in 4 operation was delayed for more than 3 days. 36 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 value. Even with sophisticated present day investigations, abdominal tenderness remains one of the most important signs of abscess.37 INTUSSUSCEPTION It has been estimated that 1% of CF patients will develop intussusception but this report was before the more effective microsphere pancreatic enzyme preparations were available.38 The main clinical features of intussusception in CF patients 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'39 despite the characteristic bull's eye appearance.40 hi our experience ultrasound is unreliable in the identification of intussusception in CF patients and a contrast enema should be an early investigation which will usually suggest the diagnosis.41 The intussusception may be chronic in CF patients.39 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. 25 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 an early stage in an attempt to rule out intussusception. Increasing local tenderness and the patient's general condition are also of paramount importance in deciding on the need for surgical intervention. PANCREATITIS A very occasional CF patient has pancreatic calcification which does not appear to have a particular clinical association.42 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 function.43'44 Cystic fibrosis should be considered in all patients with acute or relapsing pancreatitis even if

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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.45 COWS' MILK INTOLERANCE Vomiting, failure to thrive or persisting bowel problems may be due to cows' milk intolerance (CMT). The condition 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.46 However, clinical food allergy and intolerance is unusual in older CF patients even though many are atopic; it has been suggested that antigen absorption from the gut may be impaired in CF as evidenced by the fewer than expected positive RASTs to foods.47 COELIAC DISEASE Coeliac disease is well documented as occurring in CF patients48-49 and appears to be more common than in the general population. Recently 5 CF patients with well proven coeliac disease have been reported in a CF population of 1100 (1 in 220).50 A jejunal biopsy should be included in the investigations of any CF patient who has persisting bowel symptoms and/or poorly controlled malabsorption despite apparently adequate pancreatic enzyme treatment Gliadin antibodies may eventually obviate the need for jejunal biopsy but, as yet, have not been evaluated in CF patients. GIARDIASIS A cross-sectional study in the USA, using a sensitive ELISA method, showed that 28% of CF patients were positive for Lamblia giardia compared to 6% of controls.51 In our patients we have failed to identify the protozoan as a significant problem. However, there have been isolated reports of giardiasis in the UK. CROHN'S DISEASE Before the mid 80's, 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 may be related to the

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patients' increased survival.52 Also the improved recognition of Crohn's disease in children and adolescents by the availability and more frequent use of fibreoptic endoscopy may have permitted more accurate histological diagnosis in some cases. It is sound advice that: 'any patient with CF wbo does not have an obvious explanation for failure to thrive or growth failure as a result of advanced pulmonary disease or wbo fails to respond to treatment for pancreatic insufficiency needs a full work-up that includes demonstration of the anatomical status of the intestinal tract' 5 2

One would stress that the investigations would include biopsies of the gastric, duodenal and colonic mucosae for histology. There has been no CF patient recognised 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 recognised in the untreated CF patient 53 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 started.54 In CF patients referred to Leeds, 57/386 (14.8%) had experienced at least one episode of rectal 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. A sweat test should be performed in any child presenting with a rectal prolapse; in a recent series 6 (11%) of such children had cystic fibrosis.55 INTRA ABDOMINAL MALIGNANCY As the survival of CF individuals improves, there have been a number of reports of malignant disease including adenocarcinoma of the ileum,56 carcinoma57 and adenocarcinoma of the pancreas58 and carcinoma of the extrahepatic biliary system.59 The increasing frequency of these reports have been advanced as a reason for routine CF postmortem examinations.

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CONCLUSIONS The CF patient may suffer from any of the intra-abdominal conditions which occur in the non-CF individual. The improved survival and better control of the symptoms of malabsorption have permitted more frequent recognition of other gastrointestinal disorders. It is important that these are considered both as the main cause of the patient's 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. A CF patient with persisting abdominal symptoms and signs, despite adequate doses of pancreatic enzymes, deserves full gastrointestinal investigation both to assess the adequacy of pancreatic enzyme replacement therapy and to exclude other causes of the symptoms and signs. REFERENCES 1 Littlewood JM. Gastrointestinal complications in cystic fibrosis. J R Soc Med 1992 (in press) 2 Littlewood JM. Pancreatic enzymes in cystic fibrosis In: Lankisch PG, ed. Pancreatic enzymes in health and disease. Beilin: Springer-Verlag, 1991: pp 177-189 3 Bendig DW, Seilheimer DK, Wagner ML, Ferry GD, Harrison GM. Complications of gastroesophageal reflux in cystic fibrosis. J Pediatr 1982; 100. 536-540 4 Scott RB, O'Laughlin EV, Gall DG Gastroesophageal reflux in patients with cystic fibrosis. J Pediatr 1985; 106: 223-227 5. Stringer DA, Sprigg A, Joudis E et al. The association of cystic fibrosis, gastroesophageal reflux, and reduced pulmonary function J Can Assoc Radjol 1988; 39: 100-102 6 Feigelson J, Girault F, Pecau Y. Gastroesophageal reflux and esophagius in cystic fibrosis. Acta Paediatr Scand 1987; 76: 989-990 7 Cucchiara S, Santamaria F, Andreotb MR et al. Mechanisms of gastro-oesophageal reflux in cystic fibrosis. Arch Dis Child 1991; 66: 617-622 8 Malfroot A, Dab I. New insights on gastro-oesophageal reflux in cystic fibrosis by longitudinal follow up. Arch Dis Child 1991; 66 1339-1345 9 Dab I, Malfroot A. Gastro-oesophageal reflux: a primary defect in cystic fibrosis. Scand J Gastroenterol Suppl 1988; 143: 125-131 10 Atennan K. Duodenal ulceration and fibrocystic disease of the pancreas. Am J Dis Child 1961; 101 210 11 Oppenheimer EH, Esteriey JR. Pathology of cystic fibrosis. Review of the literature and comparison with 146 autopsied cases. Perspect Pediatr Pathol 1975, 2: 241-278 12 Przyklenk B, Bauerfeind A, Bertele-Harms RM et al The significance of Helicobacter pylori in patients with cystic fibrosis. 17th European Cystic Fibrosis Conference, Copenhagen, 1991, Poster No 72: p85 13 Zentler-Munro PL Pancreatic insufficiency and cystic fibrosis. Current opinion in gastroenterology 1989; 5: 706-710 14 Gilbert J, Kelleher J, Littlewood JM, Evans DF. Ileal pH in cystic fibrosis. Scand J Gastroenterol 1988; 23

Cystic fibrosis: gastrointestinal complications.

An individual who has cystic fibrosis (CF) may suffer from gastrointestinal problems related to inadequately controlled intestinal absorption secondar...
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