Colonic strictures in cystic fibrosis - Europe PMC

JOURNAL OF THE ROYAL SOCIETY OF MEDICINE

Supplement No. 25

Volume 88

1995

Colonic strictures in cystic fibrosis Professor J A Dodge MD FRCP(L,E,I)

Dr C Macpherson MRCGP MRCP

J R Soc Med 1995;88(Suppl. 25):3-8

PAPER READ TO SECTION OF PAEDLATRICS, 25 OCTOBER 1994

Keywords: cysticfibrosis; colonic stiacture; abdominal pain

INTRODUCTION

Pancreatic insufficiency is a characteristic, though not invariable, feature of cystic fibrosis, leading to many of the gastrointestinal manifestations: steatorrhoea, flatulence, abdominal pain, distal intestinal obstruction syndrome and rectal prolapse. These are usually improved by adequate pancreatic supplementation, particularly successfully with microsphere preparationsl 2. With the advent of the high lipase microsphere, a new era of improved management of pancreatic insufficiency was thought to have dawned. Concentrated packages of enzymes meant a more convenient preparation for the patient and those who cared for them hoped to see fewer gastrointestinal symptoms and better compliance. Unfortunately our optimism has recently been dampened by reports earlier this year of colonic stricture formation occurring in association with high lipase formulations3 Is there a tenuous or definite link between the two? The question leads us to review the pathophysiology of the gastrointestinal tract in cystic fibrosis and the pharmacology of enteric coated microspheres. Current hypotheses on the development of colonic strictures will then be discussed. PATHOPHYSIOLOGY

The biochemical defect in the CF cell is one of chloride transport. Ineffective Cl- handling at the cell membrane leads to an abnormality of water transport. At the surface of epithelial cells secretions are consequently more viscous than normal. Within the pancreas abnormal ductular function leads to the production of a scanty, viscid fluid that is low in bicarbonate. Acinar function becomes impaired as a result of ductal blockage and the secretion of enzymes is hampered. Duodenal aspirates from patients with cystic fibrosis are viscous, of small volume and contain low concentrations of pancreatic enzymes and bicarbonate4. Incomplete neutralization of acid contents from the stomach results. The persisting acidic conditions in the upper small bowel lead to bile salt precipitation and defective lipid

Deparbnent of Child Health, The Queen's University of Belfast, Institute of Clinical Science, Grosvenor Road, Belfast BT12 6BJ, UK

solubilization. However, although the duodenal and upper jejunal pH is low, most of the small bowel is at pH 6 or more. This will allow release of active enzymes from the microsphere preparations further down the alimentary tract. The small bowel transit time is prolonged in CF when compared with controls5. The luminal surface of the small intestine is covered by a thick layer of adherent mucus which plugs the mucosal crypts and goblet cells. It has been suggested that this presents a physical barrier to fatty acid absorption, in addition to the maldigestion of fat consequent on absence of pancreatic lipase. Mucus layers are protective barriers on epithelial surfaces, and the CF gut is no exception. Defects within this layer in association with breakages in underlying epithelium may permit the entry of noxious substances to the submucosa. In the light of colonic stricture formation, it has been suggested that such an event may lead to submucosal inflammatory changes and initiate a cyde of repair and fibrosis. The ileocaecal region is the most common site for complications with the CF gut. However, even in healthy subjects it remains one of the least explored areas of the gastrointestinal tract. Some functions of the ileum are quite specialized, active absorption of bile acids and vitamin B12 being the most obvious examples. In addition, the ileocaecal valve separates the abundant and complex flora of the large bowel from the less contaminated ileum. Thus the large and small bowels are compartmentalized by the ileocaecal junction which inhibits a segment of tonic pressure; the zone relaxes with distension of the ileum and contracts with distension of the proximal colon. Another function of the ileocaecal area is to regulate the transmission of fluid from the small to large bowel. The rapid infusion of fluid into the caecum transiently impairs the capacity of the colon to compensate and the ileocaecal valve may act as a brake on such flow6. Studies with pH sensitive capsules in CF patients have shown that the normal distinct transition from small to large intestine may be absent, the ileum and caecum appearing to function as a common dhamber in respect of pH5. It is of great interest that the problems of meconium ileus, distal intestinal obstruction syndrome and now colonic strictures emanate from the ileocaecal region. Specific pathophysiology in the uncomplicated large bowel in CF is limited to the histological findings of large dilated submucosal crypts packed with mucus7.

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COMPLICATIONS

Distal intestinal obstruction syndrome (DIOS)

Meconium ileus The accumulation of meconium starts in the distal small intestine in the fourth month of gestation. As gestation proceeds, the meconium normally moves to the colon, where it is continuously mixed by backward and forward movements. In 95% of newborn infants the first passage of meconium occurs within 24 h after birth. Meconium ileus is the presenting symptom in 10-15% of infants with cystic fibrosis, and is the earliest clinical manifestation. The clinical and radiological features of meconium ileus are those of small bowel obstruction. The colon, called 'microcolon', is small and unused. The distal ileum is small too but somewhat larger than the colon and contains hard pellets of inspissated meconium. The more proximal ileum is very dilated, the wall is hypertrophied and an intraluminal collection of thick meconium is present. In the jejunum there is less dilation and intestinal contents are more fluid8. The meconium in this condition is abnormal when subjected to chemical analysis. The water content is decreased, viscosity is increased and there is an increased content of albumin and dissacharidases. Sodium, potassium, magnesium, copper, zinc and manganese are reduced and calcium is greatly increased in concentration within the abnormal meconium. The differential diagnosis includes Hirschsprung's disease, intestinal volvulus, ileal atresia, and other surgical emergencies. A significant proportion of infants with meconium ileus have peritonitis, volvulus or atresia. Initial management involves a full assessment of clinical status, including a measurement of serum electrolytes while securing intravenous access for adequate hydration. Gastrografin enemas may be administered by a skilled paediatric radiologist in cases of uncomplicated meconium ileus. Surgery is frequently needed to relieve the obstruction. It is vital to optimize the overall condition of the infant prior to surgery and total parenteral nutrition is often established in our centre before going to theatre. Good post-operative care involves close liaison between surgical and medical teams. In many cases the creation of a double-barrelled enterostomy or a Bishop-Koop operation is the initial surgical procedure and the anatomy and motility of the defunctioning distal colon can then be assessed radiologically before anastomosis is attempted. Increasingly, paediatric surgeons are now performing primary anastomosis after intestinal lavage, with or without resection as necessary. Resection of areas of gangrenous small bowel or the anastomosis of a Bishop-Koop operation may occasionally be followed by a surgical stricture, and if exploratory surgery is required at a later date the bowel is characteristically thickened and fibrotic at the point of narrowing.

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Distal intestinal obstruction ('meconium ileus equivalent') is the term used to describe partial or complete obstruction of the CF gut in older children and adults. It results from obviously viscid mucofaeculent material in the terminal ileum and right colon, where the faecal stream is usually liquid. Strictly interpreted the term only describes acute obstruction, but it is more generally used to describe the varied clinical disorders which have, as their basic pathological feature, abnormal intestinal contents partially or completely obstructing the small or large intestine or both. The usual clinical presentation is one of chronic or recurring abdominal pain, some distension and relative constipation. The cardinal clinical sign is a soft, mobile nontender mass in the right iliac fossa. Precipitating factors may be a change in the dosage of pancreatic enzymes, a change in diet, dehydration or a respiratory exacerbation. In many cases no precipitating factor can be identified. Abdominal X-ray will show a characteristic bubbly appearance in the ileum and right colon, and with complete obstruction, fluid levels within the small bowel can be seen on an erect abdominal film. Management is largely dependent on the type of presentation. With complete obstruction, nasogastric drainage of stomach contents is required in addition to intravenous fluid replacement. Diatrizoate (gastrografin) enemas are required to disrupt the obstructing faecal mass. Surgery must be avoided if possible. In partial obstruction oral gastrografin in addition to N-acetylcysteine and stool softeners such as lactulose are used. Gastrografin enemas may be required in resistant cases of partial obstruction. The dosage of pancreatic enzyme is reviewed, compliance with this is checked and the dose altered if necessary. For those patients in whom partial obstruction is recurrent, we maintain them on regular lactulose and N-acetylcysteine for a period of weeks. We have also used cisapride in this group of patients and found it to be helpful. The use of cisapride in improving chronic abdominal symptoms in patients with DIOS has been endorsed by dinicians in Toronto9. Occasional patients have come to laparotomy when the diagnosis was in doubt. Surgeons report that it is often impossible to detach the obstructing faecal mass from the intestinal wall without stripping the adherent mucosa. Intussusception Intussusception is a rare complication in cystic fibrosis and yet it must be considered as a differential diagnosis in the patient who presents with colicky abdominal pain and a right-sided abdominal mass. It is thought to be a complication of distal intestinal obstruction, the presumed mechanism being through a tenacious faecal bolus adherent


to the intestinal mucosa acting as the lead point of the intussusception. The most common site is ileocolic. Blood in the stools, dassically described in intussusception is not frequently noted in this group of patients. It may be difficult to diagnose this condition by ultrasound examination alone and it has been recommended that a contrast enema should be carried out at an early stage in the patient presenting with signs of obstructionl1. Should attempts at reduction under radiological control fail, surgical intervention is required. Chronic intussusception has also been recognized in the CF patientll and must be considered as a possible cause of recurrent abdominal pain. Appendicitis There is no convincing evidence to suggest that CF patients are more or less prone to appendicitis than the general population. The appendix, however, does have its own characteristic histological appearance. This indudes goblet cell hyperplasia and crypts distended with mucus. This is thought to be part of the generalized intestinal mucus hypersecretion typical of the CF gut. Appendicitis may result from blockage of the appendiceal lumen, usually by a faecolith. The appendix then becomes distended with retained secretions. Such distension may lead to impairment of vascular flow and subsequent ischaemia contributes to perforation. It is interesting to note that in all the published series of appendicitis in the CF patient to date, the diagnosis has not been made sufficiently early to prevent perforationl'. Proposed reasons for this include the higher incidence of other pathology (DIOS) and concurrent antibiotic treatment which may modify the usual inflammatory response in acute appendicitis. Usually, at operation the appendix is thickened and embedded in a dense mass of fibrous tissue. Crohn's disease The pathological findings of transmural inflammation occurring in association with epithelioid granulomata typical of Crohn's disease has recently been described in cystic fibrosis patients'2-'4. The age range of the patients was from nine to 23 years. Their presentations were varied. Many of the initial symptoms such as recurrent abdominal pain, diarrhoea,

fever, weight loss and arthralgia could justifiably be attributed to cystic fibrosis, and it was only when additional features such as perianal abscess and fistula formation developed that the differential diagnosis was extended to indude Crohn's disease. Some of the patients in the reported series required laparotomy and resection of the diseased segments. Ojeda et al.12 detailed the findings from their 23-year-old patient and described the resected colon as

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shortened by fibrosis and displaying the widespread excessive production of mucus as well as discrete areas of mucosal ulceration with fissures, transmural inflammation and multiple epithelioid granulomas characteristic of Crohn's disease. Behrens et al.13 suggested that the coexistence of cystic fibrosis and Crohn's disease was not incidental-a view supported by Lloyd-Still, who suggested that the true incidence of Crohn's disease in CF might be as high as 1%15. Bowel tumours At least four cases of adenocarcinoma of the ileum have been reported in older CF patients15. It is interesting that this rare neoplasm occurs in precisely that part of the small bowel which is affected by DIOS and meconium ileus. The literature also describes a number of CF patients with fibrous thickening of the ileal wall, and narrowing of the lumen, very similar to some of the colonic strictures reported recently. Some of these patients required surgical resection of benign tumorous lesions.

Pancreatic supplementation In recent years many changes have emerged in the management of pancreatic insufficiency in cystic fibrosis. They have largely evolved as a result of the development of the acid resistant microsphere and the subsequent progression to 'high lipase' formulations. The introduction of these products followed a major rethink on the dietary management of cystic fibrosis, with a move away from the traditional 'low fat diet' to a high energy one with normal or above-normal dietary fat. It has been estimated that patients with cystic fibrosis may need up to 11/2 times normal energy

requirements'6. High lipase enzyme preparations became available in the UK in 1992. There are four commercially available products: Creon 25000 (Duphar), Pancrease HL (Cilag), Nutrizym 22 (Merck) and Panzytrat 25000 (Knoll). Approximately two-thirds of CF patients with pancreatic insufficiency take these enzyme preparations. All contain between 22 000 and 25 000 units of lipase but their daimed protease content is more variable from 467 to 1250 BP units. Each preparation consists of enteric coated microspheres within a hard gelatin capsule. The capsule dissolves in the stomach and releases the microspheres. The enzymes should be taken just before and during the intake of food. The microspheres mix with the stomach contents, the coating around them preventing acid inactivation of lipase. To leave the stomach and pass the pylorus with solid food the microspheres must be in the range of 1.4 + 0.3 mm. Larger microspheres may have a delayed onset of action.


As the microspheres enter the duodenum and jejunum they pass into an increasingly less acid environment. Effective enzymes are released as soon as pH 5.5 has been reached. Due to ineffective release of bicarbonate from the pancreas in CF this pH is achieved further down the small intestine in cystic fibrosis. In those whose absorption remains poorly controlled cimetidine or ranitidine taken 30 min before the meals and enzymes will improve fat absorption provided an adequate amount of enzyme is

administeredI7>19. What is an adequate amount of enzyme? It has been calculated that 30 000 units of lipase are secreted per meal, which is equivalent to between one and two high lipase capsules. In practice, significantly more are often needed to control steatorrhoea. Lebenthal has recently summarized some of the factors which affect bioavailability of pancreatic enzymes in cystic fibrosis20. They include enzyme source (porcine, bovine, fungal), manufacturing process, stability, enteric coating, formulation and particle size. Host factors include gastric emptying, acid output, time of ingestion in relation to meal, small intestinal pH, motility, and the physiochemical properties of the succus entericus20. The complexity of the physiological response of the human exocrine pancreas to meals is virtually impossible to reproduce, and it is not surprising that increasing doses of pancreatin are not matched by a corresponding increase in effectiveness: Imore is not necessarily better'. Recently it has been found that in vitro enzyme potency varied markedly between batches of the same brand, and that there was also a decline of up to 20% in amylase, lipase and trypsin activity over an eight-month period of each batch2l. When fresh from the factory, pancreatic capsules may contain up to twice the stated lipase activity22. A lipase 'dose' not exceeding 3000 units/kg/meal (and by implication a smaller dose for snacks) has been suggested20. This is higher than the dose used in most US centres. Within our own centre enzyme doses have been titrated against symptoms such as abdominal pain and stool frequency and on average in the older patient we use six high lipase capsules for a main meal and three with a snack which approximates the proposed upper limit. For those who seem to be requiring yet higher dosages we carefully review their compliance and timing of enzyme taking in relation to meals, before commencing an H2-antagonist (cimetidine). As the regional CF centre for children and adults in Northern Ireland we were greatly pleased with the improvements in compliance and control of symptoms heralded by the introduction of high lipase enzymes. However, it has often been shown that there is little correlation between reported symptoms and the degree of steatorrhoea. If

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patients are not thriving or losing weight, despite enzyme doses usually regarded as adequate, full investigation including a fat balance is indicated. Colonic stricture formation In 1993, a small duster of patients with cystic fibrosis presented to a single paediatric unit, Alder Hey Hospital, Liverpool with clinical features of intestinal obstruction. The ages of the patients ranged from two to 13 years and all were male. Initially they were all thought to have distal intestinal obstruction syndrome, but they failed to respond to medical management. Radiological techniques, including ultrasound scans and barium enemas revealed that all had narrowing of the lumen of the ascending colon. At surgery the essential findings were thickened rigid areas of the bowel with severe constrictions of the lumen. Histology of the resected specimens was distinctive. All had sub-mucosal fibrosis without the inflammatory features one would expect in Crohn's disease. Some had an eosinophilic infiltrate. There were changes in blood vessels which suggested that ischaemia might be a contributory factor. In some, there was subserosal fibrosis. American reports of similar lesions (below) noted an increase in the ganglion cells of Meissner's plexus similar to that seen in Hirschsprung's disease. These patients were reported by Smyth et al. in the Lancet3 and it was suggested that the lesions may be related to an increase in pancreatic enzyme supplementation which had occurred in all patients during the previous 12-18 months. A similar case had occurred in Copenhagen in 1993, and the publicity surrounding these cases brought to light several others, including one from the Brompton Hospital, London, one from Stoke-on-Trent, England, one from Nottingham, England and a further instance from Sheffield, England. This last patient was of particular significance, because it had occurred in 1988, i.e. prior to the introduction of high strength enzyme preparations. Further instances were soon reported from the United States. In Minneapolis, two such patients had presented, only one of whom was taling the high strength enzyme supplements. By March 1994, the American CF Foundation had identified 14 cases of colonic stricture, which, like the British cases were all in children. Most had a high lipase intake in excess of the 10 00015 000 units/kg/day recommended and substantially higher than the lipase intake in a control group of CF patients who had surgery for other bowel disorders23. In the UK, following the report in the Lancet, the Committee on Safety of Medicines cautioned against the use of high strength lipases. Surprisingly only a minority (40%) of CF centre physicians initially accepted that enzymerelated stricturing was a significant problem. Relatively more adult centre physicians dtan paediatricians had implemented the directive (50% versus 20%) although


strictures had only been reported in children23. The reluctance to change back to the older formulations probably derives from an inability to visualize a definite mechanism by which high strengh lipases could create such a problem, together with the favourable effects of high-lipase enzymes in the majority of patients. Colonic stricture formation: a historical perspective Stenosis of the bowel as a result of drug-induced injury is not a new phenomenon. In 1964 Lindholmer et al.24 reported four cases that required surgery for ileus caused by a short stricture of small bowel. Microscopy in these cases revealed

well defined ulceration with non-specific, vascular granulation tissue. The underlying submucosa was sclerotic and the adjoining mucosa was severely oedematous. No patterns characteristic of Crohn's disease were discernible. Further work carried out by Baker established the cause as being potassium chloride tablets given in conjunction with thiazide diuretics25. In 1959 enteric coated forms of KCl and thiazide entered the drug market and in this convenient form showed a rapid rise in popularity. Shortly thereafter the first cases of KCl induced ulcers of the small bowel began appearing. It was established that the coating material per se did not have ulcerogenic properties, but rather it was the uniformity in effectiveness with which it released its contents at a specific pH level that caused a high concentration effect26. It was also noted that the susceptibility of the gastrointestinal tract to the effects of noxious agents varied greatly at different levels; the reservoir organs such as the stomach being most resistant, while areas further down the gastrointestinal tract such as the ileum were more vulnerable. Can any parallels at all be drawn from this now historical experience and the recent development of colonic strictures in cystic fibrosis patients? Current hypotheses re stricture formation Van Velzen (1993, unpublished) proposed that the high strength enzymes became embedded in the retained faecal material in the caecum, and that by constant pressure and mechanical application of the obstructing bolus the active enzymes remaining in the preparation initiate or develop damage to the bowel wall, penetrating into the submucosal tissues and setting up a fibrotic reaction. In our experience in Belfast we often see undissolved pancreatic microspheres mixed with the faeces, particularly in our young patients. Are these microspheres being activated much firther down the gastrointestinal tract than we used to think? Are we producing an abnormally high concentration of pancreatic enzymes in the ileocaecal and ascending colon segments? Taking into account the slower

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bowel transit time, the predisposition to constipation and subclinical distal intestinal obstruction syndrome, any active enzymes in the faecal material would have an increased time of contact with the bowel wall. The mucinous coat adherent to the intraluminal surface of the bowel should prevent damage to the underlying epithelium and submucosa. It has been suggested that an episode of distal intestinal obstruction may be the initiating insult in the formation of colonic strictures. Perhaps when an adherent mass of mucofaeculant material is shifted either with normal peristalsis, enhanced enzyme activity or even the action of gastrografin, epithelium may be stripped from the intraluminal surface. Such a denuded area would then be vulnerable to any noxious substances present within the bowel lumen, including active enzymes, gastriografin or indeed even the faecal material itself. Inflammatory processes may then involve the underlying submucosa. Healing would result in fibrosis, and perhaps stricture formation. Unrelated to cystic fibrosis, a recent paper by Scheppach27 reviewed the effects of short chain fatty acids on gut morphology and function. Short chain fatty acids (SCFAs) are the products of colonic bacterial degradation of unabsorbed starch and non-starch polysaccharide (fibre). They are important anions in the colonic lumen, affecting both colonocyte morphology and function. There is evidence that epithelia lining the intestinal tract rely more on luminal than on vascular energy supply. The colonic epithelial cells are fuelled by the short chain fatty acids derived from bacterial carbohydrate (dietary fibre, starch) fermentation. If these are not present diminished mucosal nutrition may lead to mucosal atrophy, diminished absorption and eventually to colitis. Short chain fatty acids are absorbed along a concentration gradient and their transport is coupled with Na+ absorption. In this way they act as an antidiarrhoeal agent. Antibiotics reduce the concentration of short chain fatty acids in the bowel which may be the mechanism by which antibiotics cause diarrhoea. Very high doses of pancreatic enzymes appear to cause a non-specific colitis even before strictures develop (Koch, 1994, personal communication), and the effect of a shortage of shortchain fatty acids resulting from antibiotic treatment could surely be additive. Finally, the histological appearances of the strictures are suggestive of ischaemia. They are remarkably symmetrical, even circumferential, and, oddly, sometimes show involvement of the submucosa and serosa with sparing of the smooth muscle coat. A similar serosal thickening is seen in resected bowel following intussusception, which is another clinical condition occurring in the same age group as strictures, and a recognized complication of CF. Would it be too fanciful to imagine that the repeated pressure effects of an inspissated and tethered bolus of enzyme-containing faecal material could act like an intussusceptum, or perhaps

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even be associated with a mild degree of true intussusception, and produce concentric ischaemia? The presence of high concentrations of active enzymes, with proteases having a more important role than lipases, would be an important, perhaps essential, contributory factor. Studies have shown that in experimental ischaemic lesions of the colon in dogs, ligation of the pancreatic duct had a marked protective effect-indicating that pancreatic enzymes contribute to ischaemic injury28. Epidemiological studies, set up by the Medicines Control Agency and the companies marketing enzymes, are in progress in 1994 to determine whether there is a true association between high enzyme and colonic strictures. If so, the pathophysiology can only be teased out by animal studies, but it is to be hoped that the warnings of potential risk will ensure that no further cases will occur among our CF children. REFERENCES I Zentler-Munro PL. Cystic fibrosis, a gastrointestinal cornucopia. Gut 1987;28:1531-47 2 Stern RC, Izant RJ, Boat TF, et a). Treatment and prognosis of rectal prolapse in cystic fibrosis. Gastroenterology 1982;82:707-10 3 Smyth RL, Van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures of ascending colon in cystic fibrosis and high strength pancreatic enzymes. Lancet 1994;343:85-6 4 Park RW, Grand RJ. Gastrointestinal manifestation of cystic fibrosis: A review. Gastroenterology 1981;81:1143-61 5 Gilbert J, Kelleher J, littlewood JM, Evan DF. Ileal pH in cystic fibrosis. ScandJ Gastroenterology 1988;23(Suppl J):132-4 6 Quigley EMM, Boro TJ, et a]. Motility of the terminal ileum and ileocaecal sphincter in healthy humans. Gastroenterology 1984;87:857-66 7 Parkins RA, Eidelman S, et a). The diagnosis of cystic fibrosis by rectal suction biopsy. Lancet 1963;ii:851-6 8 Eggermont E. The role of the small intestine in cystic fibrosis patients. Acta Paediatr Scand 198S;Suppl 317:16-21 9 Koletzko S, Corey M, Ellis L, Spino M, Stringer D, Dunie P. Effects of cisapride in patients with cystic fibrosis and distal intestinal obstruction syndrome. J Pediatr 1990; 115:815-21 10 Smith HL, Weller PH, Gornall P, Chapman S, Jones TJ. Pitfalls in the diagnosis of appendix abscess in cystic fibrosis. i R Soc Med

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11 Mulvihill DM. Ultrasound findings of chronic intussusception in a patient with cystic fibrosis. J Ultrasound Med 1988;8:353-55 12 Ojeda VJ, Leritt S, Ryan G, Lawrence BH. Cystic fibrosis, Crohn's colitis and adult meconium ileus equivalent. Dis Colon Rectum

1986;29:567-71 13 Behrens R, Segerer B, Bowing B, Bender SW. Crohn's disease in cystic fibrosis. J Pediatr Gastroenterol Nutr 1989;9:528-31 14 Dalzell AM, Heaf DP, Carty H. Pathology mimicking distal intestinal obstruction syndrome in cystic fibrosis. Arch Dis Child 1990;66:540-1 15 Lloyd-Still JD. Cystic fibrosis, Crohn's disease, biliary abnormalities, and cancer (Editorial). J Pediatr Gastroenterol Nutr 1990; 11 :434-7 16 Dodge JA. The nutritional state and nutrition. Acta Paediatr Scand 1985;Suppl 317:31-7 17 Gow R, Bradbear R, Francis P, Shepherd R. Comparative study of varying regimens to improve steatorrhoea and creatorrhoea in cystic fibrosis: effectiveness of an enteric coated preparation with and without antacids and cimetidine. Lancet 1981;ii:1071-4 18 DiMango EP. Controversies in the treatment of pancreatic exocrine insufficiency. Dig Dis Sci 1982;27:481-4 19 Kraisinger M, Hochhans G, et al. Clinical pharmacology of pancreatic enzymes in patients with cystic fibrosis and in vitro performance of microencapsulated formulations. J Clin Pharmacol 1994;34: 158-66 20 Lebenthal E. High strength pancreatic exocrine enzyme capsules associated with colonic strictures in patients with cystic fibrosis: "More is not necessarily better". J Pediatr Gastroenterol Nutr 1994;18:423-5 21 Thomson M, Clague A, Cleghorn GJ, Shepherd RW. Comparative in vitro and in vivo studies of enteric-coated pancrelipase preparations for pancreatic insufficiency. J Pediatr Gastroentarol Nutr 1993;17:407-13 22 O'Hare MMT, McMaster C, Dodge JA. Stated versus actual lipase activity in pancreatic enzyme supplements: Implications for clinical use. J Pediatr Gastroenterol Nutr 1995 (In press). 23 Taylor CJ. Colonic strictures in cystic fibrosis. Lancet 1994;343:615-6 24 Lindholmner B, Nyman E, Raf L. Non-specific stenosing ulceration of the small bowel-A preliminary report. Acta Chir Scand 1964;128:31011

25 Baker DR, Schrader H, Hitchcock CR. Small bowel ulceration apparently associated with thiazide and potassium therapy. JAMA 1964; 190:134-8 26 Lachmann L, Barret W, et al. The in vivo effectiveness of enteric film coating applied to hydrochlorothiazide potassium chloride tablets by a programmed automated coating process. Curr Ther Res 1964;6:491 27 Scheppach W. Effects of short chain fatty acids on gut morphology and function. Gut 1994;Suppl 1:535-8 28 Bounons G. Acute necrosis of the intestinal mucosa. Gastroenterology

1982;82:1457-67