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BACKGROUND: The objective of the study was to determine whether ursodeoxycholic acid (Ursodiol) is protective against ibuprofen (IBU)-induced enteropathy. METHODS: Using the chronically catheterized rat model, IBU (60 mg/kg body weight per day) was infused via the gastric catheter twice daily. Pancreatic enzyme (PE; 10,000 U lipase/kg body weight per day) and Ursodiol (10 mg/kg body weight per day) in two doses were infused via the duodenal catheter. Rats were assigned to one of six treatment groups and were administered treatment for 20 days: control, IBU, PE, IBU + PE, IBU + Ursodiol, and IBU + PE + Ursodiol. The entire jejunum, ileum, cecum, and colon were available for histologic analysis using previously described techniques. RESULTS: Addition of Ursodiol to high-dose IBU and normal doses of PE showed a significant reduction in the percentage of rats with ulcers (P < 0.05), total number of serositis events (P < 0.01), total number of severe ulcers (P < 0.001), and an absence of ulcers in the large intestine. CONCLUSIONS: Ursodiol, the drug of choice for the treatment of cystic fibrosis liver disease, may offer a safe method of using high-dose IBU in these patients by ameliorating the enteropathy.

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BACKGROUND: High-dose ibuprofen therapy limits the progression of lung disease in patients with cystic fibrosis. However, ibuprofen increases intestinal permeability, which potentiates intestinal damage caused by high-dose pancreatic enzyme treatment, as was shown in a previous study by this group. In the present study, the combined effects of ibuprofen and pancreatic enzyme treatment on the intestine and liver were examined. METHODS: Using a chronically catheterized rat model, high-dose ibuprofen (60 mg/kg x day in two doses), with or without pancreatic enzyme treatment was infused into gastric and duodenal catheters, respectively, for 20 days. Six groups were studied: control group; ibuprofen treatment alone; pancreatic enzyme treatment alone (two groups: normal dose, 10,000 U lipase/kg x day and high dose, 40,000 U lipase/kg x day); and ibuprofen combined with pancreatic enzyme (two groups: ibuprofen with high-dose pancreatic enzyme and ibuprofen and low-dose pancreatic enzyme). After treatment, rats were autopsied, and complete histologic analyses of the entire intestine and liver were performed. RESULTS: Ibuprofen caused mild ulceration of the small intestine in 50% of rats. Pancreatic enzyme treatment alone did not induce ulceration of the intestine. The combination of pancreatic enzyme and ibuprofen treatment increased the severity of the ulcers in the small intestine but not the number of ulcers or the percentage of rats affected. Ibuprofen treatment alone did not cause ulcers in the large intestine, but with the addition of pancreatic enzymes, ulceration and fibrosis were present. CONCLUSIONS: Ibuprofen at doses used to limit progression of cystic fibrosis lung disease caused enteropathy in 50% of rats. There was synergism between ibuprofen and pancreatic enzyme treatment in the production of severe ulcers. Ulcers in the cecum and colon were increased with combined ibuprofen and pancreatic enzyme treatment compared with incidence in control animals.

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An epidemic of fibrosing colonopathy, a new disease caused by the prolonged administration of excessive doses of pancreatic enzymes, was first reported in 1994. More than 60 cases were known to occur worldwide before dosage guidelines were enforced. Predisposing factors were young age, previous intestinal surgery, meconium ileus equivalent, and use of H2 blockers, corticosteroids, and DNase. Abnormal features included foreshortened colon, strictures, marked submucosal fibrosis, ascites, and nodular hyperplasia of the liver. Histologic examination showed eosinophilia, mild cryptitis, epithelial regeneration, and widespread interruption of the muscularis mucosa. These findings are distinct from, but share many of the features of, those of Crohn's's disease and ischemic bowel disease. The pathogenic mechanisms remain unknown.

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BACKGROUND: Fibrosing colonopathy in cystic fibrosis occurs in children 2 to 7 years old and is associated with excess doses of high and regular strength lipase pancreatic enzymes, given for more than 6 months. A rat model was developed to study the effects of excessive doses of pancreatic enzymes equivalent to those producing fibrosing colonopathy in cystic fibrosis patients. METHODS: Five groups of animals were studied after administration of different combinations of pancreatic enzymes, oleic acid, and reserpine. RESULTS: Pancreatic enzymes alone produced minimal damage to the intestine and none to the liver. Excessive doses of pancreatic enzymes in combination with agents that increased intestinal permeability (oleic acid, reserpine) were associated with intestinal eosinophilia and necrosis of the jejunoileal muscle layer and inflammatory nodules in the liver, which increased with duration of insult. CONCLUSIONS: Increased intestinal permeability potentiates damage to the intestine caused by excessive pancreatic enzyme dosage. It is a characteristic of cystic fibrosis that may increase vulnerability to fibrosing colonopathy.

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BACKGROUND: Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. METHODS: Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. RESULTS: We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. CONCLUSIONS: In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.

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UNLABELLED: Essential fatty acid (EFA) deficiency is a predisposing factor for pulmonary infection with Staphylococcus aureus and Pseudomonas aeruginosa, the two major pathogenic microorganisms in cystic fibrosis (CF). OBJECTIVE: The goal of this study was to investigate the essential fatty acid status of CF patients from infancy to 20 years old. MATERIALS AND METHODS: Plasma fatty acid profiles for phospholipid (PL) were determined for cord (n = 6), 4 months (n = 40), 16 months (n = 25), 3 y (n = 8), 5-10 y (n = 10), and 10-20 y (n = 10) aged CF patients and compared to their respective control; cord (n = 22), 1-36 months (n = 38) and adult (n = 100). Significance was established by Student's t-test (p < 0.05). RESULTS: The plasma PL fatty acid profile for all CF patients, except cord, revealed consistent deficiency in omega 3 and omega 6 EFAs. These deficiencies were most marked at infancy and more pronounced for patients with meconium ileus. CONCLUSIONS AND RELEVANCE: EFA deficiency may contribute to the predisposition of CF infants to develop respiratory disease and to the excess cytotoxic activity found in bronchoalveolar lavage fluid at 2 months of age in the majority of screened infants.

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Excessive dosage of pancreatic enzymes in cystic fibrosis (CF) patients can be associated with irreversible colonic stricture. Predisposing factors include a young age group, previous intestinal surgery, and prolonged administration of high-dose lipase products. Prestricture symptoms include abdominal pain, diarrhea, and hematochezia. Pathological signs are ischemic denudation of the epithelium with reepithelialization, mild chronic inflammation, and extensive collagen synthesis with mural fibrosis. The lesion is distinct from Crohn's disease. Its pathophysiological mechanisms remain unknown.

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Advances in investigative techniques have led to increasing reports of Crohn's disease in CF patients. A retrospective review of the literature on IBD in CF showed findings characterized by ileocolitis with fistula formation; 83% required surgery. A prospective survey of 11,321 CF patients attending 49 CF centers revealed 28 with IBD (25 Crohn's, three ulcerative colitis), ages 4-20 years, mean 15.6 years. The prevalence rate of IBD (247/10(5)) was 7x controls and was accounted for by Crohn's disease (221/10(5)) which was 17x controls. The mechanisms that predispose CF patients to Crohn's disease are discussed.

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UNLABELLED: Intra- and extrahepatic impairment of biliary drainage is important in the pathogenesis of liver disease in cystic fibrosis. Distal common bile duct obstruction is reported to occur in 13% to 96% of these patients. Between 1975 and 1993, 17 of 372 children (4.5%) with cystic fibrosis attending The Children's Memorial Medical Center in Chicago had liver disease based on clinical and laboratory findings. METHODS: Hepatobiliary scintigraphy (HBS) with 99mTc-DISIDA was performed on 12 of the 17 children (mean age at the time of exam was 9 yr, with a range of 1 mo to 21 yr). RESULTS: All had hepatomegaly, four had splenomegaly and two had bleeding esophageal varices. Twenty HBS exams on these 12 patients documented nonvisualization of the gallbladder in 7, dilated intrahepatic ducts in 6 (only the left lobe was involved in 3 patients), nonvisualization of bowel in two, delayed peaking time in the liver (> 10 min) in four patients, and delayed clearance from the liver parenchyma (T1/2 > 20 min) in 11. There appears to be a spectrum of abnormal HBS findings in cystic fibrosis patients with liver disease. These are delayed clearance of liver parenchyma, nonvisualization of the gallbladder and dilated intrahepatic ducts with a predilection for the left lobe of the liver. These abnormal findings fluctuate in time and may not correlate with the findings on ultrasonography. CONCLUSION: Quantitative hepatobiliary scintigraphy is a valuable tool in the evaluation and management of the liver disease in this patient population.

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Acylcarnitine is low in cord blood in patients with cystic fibrosis, suggesting that fatty acid metabolism is disturbed in utero. Carnitine metabolites (total, free, short- and long-chain acylcarnitine) were measured prospectively in 23 newly diagnosed infants with cystic fibrosis treated with a carnitine-containing, predigested formula for 6-12 months. Total (p < 0.002), free (p < 0.004), and long-chain (p < 0.001) plasma concentrations of carnitines were significantly less than controls (n = 48) at diagnosis. Total and free concentrations were corrected with nutritional management, whereas short- and long-chain acylcarnitines remained unchanged. By three years of age all plasma concentrations of carnitine metabolites were significantly less than controls despite a carnitine-containing diet. Urinary carnitine metabolites were increased at diagnosis and follow-up. The physiological significance of these observations in cystic fibrosis is unknown, but could be compatible with disturbed regulatory control with resultant increased utilization.

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The fatty acid (FA) patterns of cord serum phospholipids (PLs) were examined in 4 cystic fibrosis (CF) newborns, 8 non-CF siblings, and 22 normal control subjects. Plasma from 27 newly diagnosed CF infants and 38 normal infants aged less than 2 y were studied for comparison. CF cord-blood PLs had patterns similar to those of CF siblings and to normal newborns, but the pattern for CF did not shift toward adult patterns during infancy as did patterns for normal infants. CF infants at diagnosis exhibited a deficiency pattern in which 18: 2 omega 6, 20:4 omega 6, 22:4 omega 6, an omega 3 polyunsaturated fatty acids (PUFAs) were significantly subnormal and 18:3 omega 6, total saturated fatty acids, and total monounsaturated fatty acids were significantly elevated compared with normal infants. In PLs in CF infants, although mean chain length of FAs was low, mean melting point was elevated 2.4 degrees C and double-bond index was low (both P less than 0.001), implying a significantly lessened fluidity. Nutritional supplements of both omega 6 and omega 3 PUFAs are cated.

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In 1983 we assessed the implications for hepatic transplantation programs by studying mortality from liver disease in a tertiary care children's hospital. The current study reviews the impact of orthotopic liver transplantation (OLT) on survival for the period 1984-1989. Findings showed that deaths from liver disease decreased from 9.2 to 3.8 per year. Twenty-eight infants and children were referred and underwent OLT, with a 64% survival rate. Deaths from biliary atresia, which used to account for 24% of the total, have been reduced to 4.3%. Deaths from liver failure in infancy (which decreased from 49% to 39%) still present formidable challenges for transplantation. The implications of these findings are discussed.

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Carnitine metabolites (total, free, short and long chain) were analyzed in cord blood of cystic fibrosis (n = 5), non-CF siblings (n = 7), and controls (n = 8). Total acylcarnitine (short and long chain combined) was significantly lower (less than 0.001) in CF compared to both control groups. Total and free carnitine showed no significant differences between the three groups. These findings are compatible with disturbed fatty acid metabolism in utero and may be related to the increased energy expenditure characteristic of CF infants.

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