In this issue of the Journal, Serban et al. (1) report the case of an infant, born at 38 weeks gestation, who presented on the second day of life with intestinal obstruction and failure to pass meconium. A Gastrografin enema revealed a typical microcolon with dilated loops of intestine and jejunum. The obstruction was relieved by conservative measures, but the infant failed to thrive. He was readmitted at 3 weeks of age with further obstruction, confirmed on contrast enema. At laporotomy, marked thickening of the proximal colon and caecum was found which on histological examination demonstrated features typical of fibrosing colonopathy (FC). A diagnosis of cystic fibrosis (CF) was established retrospectively following a post-mortem examination.
Fibrosing colonopathy is a rare condition seen almost exclusively in children with CF. The characteristic histopathology comprises submucosal fibrosis with thickening of the muscularis propria and chronic mucosal inflammation chiefly affecting the caecum and ascending colon. This leads to a fusiform narrowing and shortening of the bowel with subsequent stricture (2). The disorder was first described following the introduction of high-strength pancreatin (22-25,000iu lipase/capsule) in April 1992 (3). The availability of these new enzyme preparations led to a substantial increase in pancreatin dosage throughout the CF population, with some centers reporting mean doses of >20,000iu lipase/kg/day. In some patients usage was much higher. The pancreatin dose taken by the initial 7 patients reported by Smyth et al. ranged from 15,000–94,000IU lipase/kg/day (mean 55, 000iu lipase/kg/day). More extensive colonic involvement was seen with higher mean dosages (4). The association between FC and high dose pancreatic supplementation was subsequently shown to be dose related by case control studies from both the UK (5) and a further report from the US CF Foundation (6).
Following the recommendation by the MCA in 1994 that “unless special reasons exist, patients with cystic fibrosis should not use high-potency pancreatins” (7) and that the total dose used “should not usually exceed 10,000iu lipase/kg body weight daily” there was a dramatic decrease in cases of FC in the UK. Many centers demonstrated that pancreatin usage could be substantially reduced without affecting either weight gain or increasing steatorrhea (8,9).
Although the more conservative use of pancreatin has led to a reduction in symptomatic colonopathy, the actual aetiology of the disease remains unknown. Smyth et al. suggested that children with FC, in the 12 months before surgery, were more likely to have been exposed to pancreatin preparations containing Eudragit L30D55, an acrylic resin based on polymethacrylic acid and polyacrilic acid esters, widely used as an enteric coating. Subsequently one of the authors went on to describe a series of exploratory studies in adolescent pigs administered Eudragit L30D55 at doses of 10, 50 or 500 mg/kg/day (comparable to human intake) for seven days by caecal gavage. Seven of nine animals developed changes similar to fibrosing colonopathy (10). Similar studies of the monomer components of the Eudragit L30D55 co-polymer, at dose levels of 0.015 to 50 mg/kg/day, representing possible residues in Eudragit L30D55, did not produce comparable changes. Unfortunately, these findings have not been confirmed. Lloyd-Still et al. (11) were able to induce intestinal damage in an indomethacin-treated rat model following infusion of both Eudragit and non-Eudragit containing enzymes but Eudragit alone in doses of 50-200mg/day for 10 days via duodenal catheter failed to reproduce van Velzen's findings.
Moreover, van Velzen's data appear to conflict with previous toxicity studies. Chronic toxicity studies in cohorts of 60 rats given 200, 600, or 1,500 mg/kg body weight of dry co-polymer by gavage per day for 6 months (Eudragit L39D lacquer) have shown reduction in food consumption and loss of weight but the principal histological finding was fatty infiltration of the liver, not colonoscopy. Enteropathic changes were seen in only three animals and were believed to be secondary to local irritation caused by the finely ground lacquer. Whereas, Ghanayem, in 1985, gavaged single doses (100, 200 or 400mg/kg) of ethyl acrylate, one of the two monomers forming the methacrylic acid copolymer, to adult male rats and demonstrated dose- and time-dependent mucosal and submucosal changes in both the forestomach and glandular stomach. Multiple doses of 200mg/kg led to mucosal edema with vesicle formation, mucosal hyperplasia, and submucosal edema and inflammation (12).
This case is remarkable in that the changes of colonopathy evolved before exposure to exogenous pancreatin, a finding which supports an earlier report by Waters et al. (13) who described submucosal fibrosis on full-thickness rectal biopsy in an untreated neonate who again presented with meconium ileus. Moreover, Serban et al. suggest that 3 of 85 CF necropsies reviewed retrospectively showed evidence of FC. None of these infants had received pancreatic enzyme supplementation.
It appears that colonopathy can evolve in the absence of, although undoubtedly exacerbated by, exogenous pancreatin. The mechanism underlying this phenomenon is unclear. Histological evaluation of Serban et al.'s case reveals markers of a recent severe injury; also, evidence of submucosal vasculitis, findings previously reported in FC associated with the use of high-strength pancreatins. In this case, however, these changes evolved in the absence of pancreatic supplementation. Alternative mechanisms considered include increased intestinal permeability and the co-existence of a modifier gene, which may predispose a subgroup of infants with CF to develop FC following exposure to endogenous pancreatin.
Whatever the cause of colonopathy, the disorder evolves in a bowel that is both structurally and functionally abnormal. Ultrasound studies show both intestine and colon wall thickness is increased in CF (14) and this is age related (15). The intestine has abnormal permeability (16), increased concentrations of pro-inflammatory cytokines (17), and reduced disaccharidase activities (18). The gut also demonstrates the same defective Na+ and Cl− transport seen in the airway (19). This, combined with enhanced Na+-linked glucose and amino acid absorption in the upper intestine (20), and defective bile acid induced secretion in the terminal ileum (21), will increase the viscosity of luminal contents and predispose the distal intestine to obstruction. Whether exposure of the abnormally permeable gut mucosa to viscid intestinal contents and pancreatic proteases can act as a trigger for colonopathy remains speculative. If nothing else, Serban et al.'s report highlights the uncertainly surrounding the aetiology of colonopathy more than 7 years after the original case reports.
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