Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy.

Abstract: Fibrosing colonopathy, a complication of cystic fibrosis, has generally been reported in young children with exposure to high doses of pancreatic enzymes. The authors report the case of a 25-year-old male with cystic fibrosis who presented with gradually progressive symptoms of bowel obstruction. Pathologic examination of the right colon revealed findings consistent with fibrosing colonopathy. This case is distinctive because of the adult presentation, and because the patient's symptoms developed long after he had discontinued taking a high-strength enzyme preparation. This case suggests that multiple etiologic factors, and not simply exposure to pancreatic enzymes, may result in fibrosing colonopathy in adults with cystic fibrosis.

Key Words: colonic diseases, cystic fibrosis, pancreatic enzymes, pancreatic insufficiency

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Gastrointestinal conditions associated with cystic fibrosis (CF) include reflux esophagitis, peptic ulcer disease, pancreatitis, hepatobiliary disease, infectious colitis, gastrointestinal cancer, inflammatory bowel disease, appendicitis, intussusception, distal intestinal obstruction syndrome (DIOS), and volvulus. A less well-known complication is fibrosing colonopathy (FCP), characterized histologically by submucosal fibrosis, and clinically by obstructive symptoms. (1,2) The etiology is poorly understood, but FCP has been attributed to injury by high daily doses of pancreatic enzymes, high-strength preparations, or their enteric coating. (3,4,5) We present the case of a 25-year-old man with FCP that is unique in two respects. First, FCP usually presents in young children; we are aware of only one other reported case in a patient as old as ours. Second, FCP usually presents 12 to 15 months after exposure to high-dose pancreatic enzyme therapy; in contrast, our patient presented 5 years after discontinuing standard doses of enzyme therapy.

Case Report

A 25-year-old man with CF was admitted to the hospital in February 2002 with persistent right lower-quadrant pain. At 6 months of age, the patient had presented with malnutrition and was subsequently diagnosed with CF. He did not have meconium ileus at birth. His genotype ([DELTA]F508/621 + 1 G-T) is associated with pancreatic insufficiency. (6) He had received various pancreatic enzyme preparations throughout his childhood (eg, Entolase HP, Pancrease MT 16, Creon 25, and Ultrase MT 12). The only high-strength preparation was Creon 25 (Solvay Pharmaceuticals, Marietta, GA), prescribed for 10 months in 1993 (when the patient was 16 years old) at a dose of one capsule per meal.

At age 19 he underwent an appendectomy for an appendiceal abscess. Shortly thereafter, he developed low-grade intermittent right lower abdominal pain, the cause of which was unclear. At about the same time, he discontinued pancreatic enzymes himself, due to their high cost. During the several years before his discontinuing pancreatic enzymes, they were prescribed according to guidelines from a consensus conference of the Cystic Fibrosis Foundation, (7) and he had not received high-strength preparations or high daily doses. Three months before the current admission, the pain became constant; symptoms did not respond to laxative therapy. Colonoscopy was unsuccessful because of poor preparation. Computed tomography of the abdomen was negative. A barium enema demonstrated a filling defect in the cecum without reflux of contrast into the small intestine (Fig. 1).

At admission, he complained of unrelenting right-lower abdominal pain and vomiting. Physical examination revealed normal bowel sounds, focal right-lower quadrant tenderness to palpation, and voluntary guarding without rebound tenderness. Laboratory studies were unremarkable. An abdominal radiograph was consistent with adynamic ileus. Upper endoscopy was normal and colonoscopy was not attempted again. Computed tomography of the abdomen demonstrated a slightly thickened ascending colon, and pancreatic atrophy.

Because of continuing pain, nausea, and vomiting, he underwent exploratory laparotomy on the fourth hospital day. Intraoperatively, the surgeon palpated a mass in the cecum. A right hemicolectomy was performed. On opening the resected specimen, the surgeon initially believed that the patient had a cecal diverticulum with a large amount of inspissated stool and mucus. However, examination of the gross specimen by the pathologist revealed redundant hypertrophic mucosal folds that were responsible for the surgeon's impression of a cecal diverticulum, and presumably corresponded to the filling defect on barium enema. Microscopic examination revealed submucosal edema and fibrosis, consistent with FCP (Fig. 2). The patient's symptoms gradually improved postoperatively, and his symptoms have not recurred during one year of follow-up.

Discussion

FCP generally presents in young CF patients within 12 months of starting high-dose pancreatic enzyme replacement therapy. Symptoms are usually those of intestinal obstruction, but patients may also have bloody diarrhea, abdominal pain, and anorexia. (1,2) FCP usually spares the rectum, and may be either segmental or pancolonic. (2) The gold standard for diagnosis of FCP is biopsy. Characteristic histologic features include submucosal fibrosis, disruption of the muscularis mucosa, mild inflammation with or without eosinophils, and cryptitis. (1,4,7) The most common contrast enema findings are narrowing or strictures, colonic shortening, and loss of haustra. (1) Colonoscopy may demonstrate a friable, hyperemic, edematous, stiff, or ulcerated colonic mucosa.

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The pathogenesis of FCP has not been clearly determined. Risk factors noted in case-control studies include high-dose pancreatic enzyme replacement therapy, younger age (2-13 years), history of gastrointestinal complications (DIOS, meconium ileus, colitis), prior gastrointestinal surgery, use of histamine H2-receptor blockers, corticosteroids, and recombinant human deoxyribonuclease. (2,5)

In particular, attention has focused on a possible relationship between FCP and high-dose pancreatic enzyme replacement therapy. Because pancreatic enzymes were introduced before the 1938 Food, Drug, and Cosmetic Act, they were never subject to quality, efficacy, and safety testing. (7) High-strength formulations, which contained 20,000 U or more of lipase per capsule, first became available in 1991, and were intended to improve patient compliance by decreasing the number of capsules needed each day. (3) In 1994, there were three separate reports of CF patients with symptomatic colonic submucosal fibrosis, all of whom had been begun on high-strength enzymes in the 12 to 20 months prior to diagnosis. (8-10) In that same year, pharmaceutical companies withdrew high-strength preparations from the market.

Some authorities have also speculated as to whether all high-dose pancreatic enzymes are associated with FCP, or only those containing Eudragit L30D55 in the enteric coating. Eudragit is a methacrylic acid and ethylacrylate copolymer in the enteric coating. (11) It protects enzyme-containing microtablets from dissolving until pH is less than 5.5, and thus allows the enzymes to resist inactivation in the stomach. Eudragit-containing preparations include Ultrase MT (Axcan Scandipharm, Birmingham, AL) and Pancrease MT (Ortho-McNeil Pharmaceutical, Raritan, NJ), both of which our patient used. Animal studies have suggested that Eudragit may induce changes similar to FCP in humans. (11)

The Cystic Fibrosis Foundation and the FDA surveyed CF centers to determine their experience with FCP from 1991 through 1993; 45 cases were reported, 15 of which met a formal case definition. (12) Since then, additional case reports have appeared occasionally in the literature. Although FCP is primarily found in young CF patients exposed to high-dose pancreatic enzyme replacement therapy, reported cases include an adult with pancreatic insufficiency but not proven CF, (13) and infants with CF who were not exposed to pancreatic enzymes. (14,15) The average age at diagnosis of FCP is 4.2 years; (12) our patient's age of 25 years equals that of the oldest previously reported case of FCP in a CF patient. (16) It has been suggested that adults are less likely than children to develop FCP because adults use lower doses of enzymes per kilogram of body weight, and because they have a greater intestinal absorptive surface area. (5)

Our patient had low-grade pain for several years, until symptoms became intolerable. The indolent but progressive course, pathologic findings consistent with FCP, lack of response to usual medical management of DIOS, and resolution of symptoms following surgery, all suggest that DIOS alone does not adequately explain our patient's presentation. The clinical course suggests that adults with pancreatic enzyme exposure may experience a prolonged period during which symptoms of FCP are relatively indolent. However, it remains possible that mechanisms other than injury by pancreatic enzymes result in the histologic appearance of FCP in adults. For example, one group has suggested that pressure-induced ischemic necrosis due to alteration in composition of bowel mucus might cause colonic strictures. (17) Most likely, multiple factors (eg, effects of pancreatic enzymes, recurrent intestinal injury from impacted material, intestinal dysmotility, etc.) play a role in the clinical and pathologic presentation of FCP in adults. Ultrasound studies, performed primarily in children, have shown that CF patients have increased colonic wall thickness compared with controls, and that wall thickness is not necessarily correlated with enzyme dose or a history of DIOS. (18) To our knowledge, such studies have not been performed systematically in adults with CF.

Conclusion

Our patient's case of FCP is distinctive because of the diagnosis at age 25, presentation five years after discontinuing enzyme therapy, and minimal exposure to high-strength or high-dose pancreatic enzymes. Our case suggests that FCP should be considered in CF patients with abdominal pain or other unexplained intestinal symptoms, regardless of age or recent use of pancreatic enzymes. Additional research should focus on the spectrum of bowel histopathology in adults with CF who undergo abdominal surgery for obstructive symptoms.

Many a man's reputation would not know his character if they met on the
street.
--Elbert Hubbard

Accepted March 11, 2004

References

1. Reichard KW, Vinocur CD, Franco M, et al. Fibrosing colonopathy in children with cystic fibrosis. J Pediatr Surg 1997;32:237-242.

2. Schwarzenburg SJ, Wielinski CL, Shamleh I, et al. Cystic fibrosis-associated colitis and fibrosing colonopathy. J Pediatr 1995;127:565-570.

3. Powell CJ. Colonic toxicity from pancreatins: a contemporary safety issue. Lancet 1999;353:911-915.

4. Dodge JA. The aetiology of fibrosing colonopathy. Postgrad Med J 1996;72(suppl 2):S52-S55.

5. FitzSimmons SC, Burkhart GA, Borowitz D, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. New Engl J Med 1997;336:1283-1289.

6. The Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. New Engl J Med 1993;329:1308-1313.

7. Borowitz DS, Grand RJ, Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. J Pediatr 1995;127:681-684.

8. Smyth RL, van Velzen D, Smyth AR, et al. Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. Lancet 1994;343:85-86.

9. Oades PJ, Bush A, Ong PS, et al. High-strength pancreatic enzyme supplementation and large bowel strictures in cystic fibrosis [letter]. Lancet 1994;343:109.

10. Campbell CA, Forrest J, Musgrove C. High strength pancreatic enzyme supplementation and large bowel strictures in cystic fibrosis [letter]. Lancet 1994;343:109-110.

11. van Velzen D, Ball LM, Dezfulian AR, et al. Comparative and experimental pathology of fibrosing colonopathy. Postgrad Med J 1996;72(suppl 2):S39-S48.

12. Frieman JP, FitzSimmons SC. Colonic strictures in patients with cystic fibrosis: results of a survey of 114 cystic fibrosis centers in the United States. J Pediatr Gastroenterol Nutr 1996;22:153-156.

13. Bansi DS, Price A, Russell C, et al. Fibrosing colonopathy in an adult owing to over use of pancreatic enzyme supplements. Gut 2000;46:283-285.

14. Waters BL. Cystic fibrosis with fibrosing colonopathy in the absence of pancreatic enzymes. Pediatric and Developmental Pathology 1998;1:74-78.

15. Serban DE, Florescu P, Miu N. Fibrosing colonopathy revealing cystic fibrosis in a neonate before any pancreatic enzyme supplementation. J Pediatr Gastroenterol Nutr 2002;35:356-359.

16. Hausler M, Meilicke R, Biesterfeld S, et al. First adult patient with fibrosing colonopathy. Am J Gastroenterol 1998;93:1171-1172.

17. King SJ, van Velzen D, Smyth RL, et al. Strictures of the colon in cystic fibrosis. Clinical Radiology 1994;49:476-477.

18. Haber HP, Benda N, Fitzke G, et al. Colonic wall thickness measured by ultrasound: striking differences in patients with cystic fibrosis versus healthy controls. Gut 1997;40:406-411.

RELATED ARTICLE: Key Points

* Fibrosing colonopathy is a complication of cystic fibrosis that has been diagnosed almost exclusively in young children.

* Exposure to high doses of pancreatic enzymes is frequently regarded as the cause of fibrosing colonopathy.

* In this case, a 25-year-old man with cystic fibrosis developed symptoms and pathologic findings consistent with fibrosing colonopathy, long after stopping pancreatic enzyme therapy.

* Multiple etiologic factors, and not simply exposure to pancreatic enzymes, may result in fibrosing colonopathy in adults with cystic fibrosis.

Elizabeth H. Mack, MD, Allan S. Brett, MD, and Daniel Brown, MD

From the Departments of Pediatrics and Medicine, University of South Carolina School of Medicine, Columbia, SC

Correspondence to Allan S. Brett, MD, Department of Medicine, University of South Carolina School of Medicine, 2 Medical Park, Suite 502, Collumbia, SC 29203.