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Rosalind L. Smyth - One of the best experts on this subject based on the ideXlab platform.
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Intestinal inflammation in cystic fibrosis
Archives of disease in childhood, 2000Co-Authors: Rosalind L. Smyth, Una O'hea, Nicholas M. Croft, Tom G Marshall, Anne FergusonAbstract:BACKGROUND—There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS—To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with Fibrosing Colonopathy. METHODS—Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and Fibrosing Colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, α1 antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1β) were measured. RESULTS—Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1β, and interleukin 8. Similar values were obtained for the CF patients with Fibrosing Colonopathy. CONCLUSIONS—These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing Colonopathy does not appear to be associated with increased inflammation.
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Mucosal ulceration in the pathogenesis of Fibrosing Colonopathy of pediatric CF patients related to the use of high-strength enzyme preparations
1997Co-Authors: S. A. Hinchliffe, C. V. Howard, Rosalind L. Smyth, J Pope, D Van VelzenAbstract:The pathogenesis of recently described Fibrosing Colonopathy (FC) recognized in a small proportion of pediatrie cystic fibrosis patients treated with novel high-strength enzyme preparations is as yet unclear. Assessment of colonie mucosa in the 14 cases classified as FC in the United Kingdom national epidemiological study revealed sharply defined limited areas of mucosal defects suggestive of (recent) reepithelialization. Although superficial, nonspecific ulcerations have been described in nonassociated chronic inflammatory bowel disease, these lesions had as yet not been systematically studied in FC patients. The aim of the study was to define the presence and extent of focal mucosal change in the terminal ileum and colon of FC patients. Six ileocecal resection specimens of FC (confirmed by independent pathologist' review) were used for the study. Patients were 2-13 years of age at diagnosis. Two-centimeter segments of terminal ileum, cecum, colon at site of stenosis, and poststenotic ascending colon were serially sliced at 2.5 mm thick and routinely processed to paraffin. Semiserial 5-jlm paraffin sections at 500-um intervals were routinely counted and stained with H&E. Using low magnification, each section was assessed for areas of mucosal change and diagrams representing the mucosa were constructed. From these images, the fraction of surface area affected by mucosal defects was calculated using point scoring and the mean area of the ulcers for each area was calculated from the individual ulcer area as measured by point scoring technique. Surface area ulceration in various states of repair was noted in all colon 3 areas of all six patients. Terminal ileum defects were found in only two out of six patients, mean area 4.5 mm , occupying less than 3% of the surface. Cecal ulcers occupied between 5 and 11% of the surface area, mean ulcer area 4.4 mm (range 2-7 mm ). The highest values were found in the most severely stenosed segments, where ulcers occupied 8-43% of the surface and had a mean size of 2.5 mm (range 1-7 mm ).The poststenotic ascending colon showed 7-19% of the area affected and ulcers had a mean size of 3.7 mm2 (3-9 mm2). Mucosal ulceration in various stages of reepithelialization is found consistently throughout the colon of FC patients. The terminal ileum is affected in only a fraction of patients and when found to a much lesser degree. The role of these mucosal defects in the pathogenesis of FC requires urgent further research. Copyright © 1997 Taylor & Francis.
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Small and large bowel surface area related to body weight and age related to the pathogenesis of Fibrosing Colonopathy in pédiatrie patients
Pediatric Pathology & Laboratory Medicine, 1997Co-Authors: S. A. Hinchliffe, C. V. Howard, Rosalind L. Smyth, J Pope, D Van VelzenAbstract:Fibrosing Colonopathy (FC), recently described in children with cystic fibrosis taking novel high-strength pancreatic enzyme supplements, is of uncertain pathogenesis, although direct damage to the colonie mucosa by a constituent of such preparations is one possible explanation. The strict limitation of the condition to pediatrie age group patients is not explained under such a model of local toxicity. The mucosal concentration of a toxic component of the preparations is a function of total mucosal surface area. However, dosing is based on body weight and does not take into account the possibility of age-related changes in bowel surface area proportional to body weight. The presence of such a relationship might explain the age distribution of FC. At present, this information is not available in the literature. The aim of the study was to determine the relationship between small and large bowel surface area and age/body weight in man. One hundred fifty-four consecutive pediatrie and adult postmortem examinations of patients without history or evidence of bowel disease or congenital malformation were included in the study (83 males, 71 females; age 0-40 years). At autopsy the postduodenal small bowel and large bowel (cecum to rectum inclusive) were removed from the body and their lengths measured separately. Specimens were then opened longitudinally and the mucosal width was determined at 10 systematically random locations distributed equidistantly throughout their length. For each case the mean mucosal widths of small and large bowels were calculated and multiplied by their respective lengths to determine the total mucosal surface areas. Division by body weight gave the surface area/body weight ratio (SA/BW ratio) of small and large bowels. The SA/BW ratio of the small bowel does not differ significantly between birth and 40 years (mean 30.7 cm /kg, range 17.9-52.7 cm /kg). In marked contrast, the SA/BW ratio for the large bowel increases significantly during teenage years from a stable mean of 5.7 cm /kg (age 0-12 years) to41.0cm2/kg (age 19.40years) (P< .001 ). The SA/BW ratio for the large bowel is significantly less than that for the small bowel between the ages of 0 and 14 years (P< .0005). There is no significant relationship between sex and SA/BW ratio for either small or large bowels. Results suggest that in children the concentration of any potential toxin at the colonie mucosa may be five times that in the small bowel. Similarly, for the same dose per unit body weight, the concentration in a child's colon may be seven times that in an adult. We believe these results provide an explanation for the restriction of Fibrosing bowel disease in cystic fibrosis to the colon of children and support a hypothesis of local toxiciry for its pathogenesis. Copyright © 1997 Taylor & Francis.
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Fibrosing Colonopathy in cystic fibrosis.
Archives of disease in childhood, 1996Co-Authors: Rosalind L. SmythAbstract:The introduction of enteric coated pancreatic enzyme supplements in the early 1980s was undoubtedly one of the major advances in the care of children with cystic fibrosis. Further refinements in the presentation of these preparations inevitably followed, to improve patient acceptability and compliance. The emergence of Fibrosing Colonopathy took clinicians dealing with cystic fibrosis completely by surprise, and in the last two years there has been a gradual appreciation that as far as pancreatic enzyme products are concerned 'More is not necessarily better'. However, it is encouraging that, in the UK, there have been no histologically confirmed cases in children receiving high strength pancreatic enzyme preparations since July 1994. Hopefully this trend will continue and the causal factors will be defined, ensuring that this serious complication can be effectively prevented in the future.
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Fibrosing Colonopathy in cystic fibrosis: results of a case-control study
Lancet (London England), 1995Co-Authors: Rosalind L. Smyth, Una O'hea, E Burrows, Deborah Ashby, P.a. Lewis, D Van Velzen, J.a. DodgeAbstract:Abstract Summary Fibrosing Colonopathy was first described in cystic fibrosis (CF) children in 1994. We have done a nested case-control study to identify possible associations with this condition. A case ascertainment within the UK CF population to identify any cases that occurred between January, 1984, and April, 1994, found 14 cases, all under 14 years and confirmed by independent histopathological review. All had presented since April, 1993; 12 were boys and six had received some or all of their care in Liverpool. Each case was matched, by date of birth, with four controls from the UK CF Registry. Information was obtained about cases and controls from their case records and by a structured interview with the families. In the 12 months before surgery, there was an association between the occurrence of Fibrosing Colonopathy and use of high-strength pancreatic enzyme preparations. This association was dose related. Odds ratio per extra 1000 high-strength capsules was 1·45 (95% Cl 1·14-1·84). For use of protease, the odds ratio per million extra units per kg was 1·55 (1·19-2·03). For usage of individual high-strength products at any time during the 12 months before surgery some differences were observed; for Creon 25000 the odds ratio was 0·38 (0·10-1·42), for Nutrizym 22 43·4 (2·51-751), and for Pancrease HL 8·4 (1·95-36·1). These last two confidence intervals are extremely wide and compatible with these two products having the same odds ratios. Laxative use was independently predictive (odds ratio 2·42 [1·20–4·94]). We conclude that there is a dose-related association between high-strenght pancreatic enzyme preparations and Fibrosing Colonopathy.
Robert E. Kimura - One of the best experts on this subject based on the ideXlab platform.
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Indomethacin and Pancreatic Enzymes Synergistically Damage Intestine of Rats
Digestive Diseases and Sciences, 1998Co-Authors: Robert E. Kimura, V Arango, John Lloyd-stillAbstract:The use of high-dose pancreatic enzymes bypatients with cystic fibrosis was associated with thedevelopment of Fibrosing Colonopathy. Preliminarystudies indicated that the infusion of high-dosepancreatic enzymes alone did not cause intestinal damage.We hypothesized that cystic fibrosis patients thatdeveloped Fibrosing Colonopathy had increased intestinalpermeability. Our goal was to develop a rat model for pancreatic enzyme-induced FibrosingColonopathy by increasing intestinal permeability withthe use of indomethacin. Pancreatic enzymes, 150,000units/kg/day, and indomethacin, 3 mg/kg/day, alone and in combination were administered via duodenalcatheter to rats for 10 days. Indomethacin andpancreatic enzymes caused intestinal damage, resultingin significant increases in the total number of ulcers (P < 0.007), the number of severe ulcers (P< 0.003), and ulcers in the cecum and colon (P
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Indomethacin and Pancreatic Enzymes Synergistically Damage Intestine of Rats
Digestive diseases and sciences, 1998Co-Authors: Robert E. Kimura, V Arango, John D. Lloyd-stillAbstract:The use of high-dose pancreatic enzymes by patients with cystic fibrosis was associated with the development of Fibrosing Colonopathy. Preliminary studies indicated that the infusion of high-dose pancreatic enzymes alone did not cause intestinal damage. We hypothesized that cystic fibrosis patients that developed Fibrosing Colonopathy had increased intestinal permeability. Our goal was to develop a rat model for pancreatic enzyme-induced Fibrosing Colonopathy by increasing intestinal permeability with the use of indomethacin. Pancreatic enzymes, 150,000 units/kg/day, and indomethacin, 3 mg/kg/day, alone and in combination were administered via duodenal catheter to rats for 10 days. Indomethacin and pancreatic enzymes caused intestinal damage, resulting in significant increases in the total number of ulcers (P < 0.007), the number of severe ulcers (P < 0.003), and ulcers in the cecum and colon (P < 0.0007). We conclude that the combination of indomethacin and pancreatic enzymes acts synergistically to cause damage to the intestine.
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The effect of intestinal permeability on pancreatic enzyme-induced enteropathy in the rat.
Journal of pediatric gastroenterology and nutrition, 1998Co-Authors: J Lloyd-still, V Arango, Michael R. Uhing, Aldo Fusaro, Robert E. KimuraAbstract: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.
D Van Velzen - One of the best experts on this subject based on the ideXlab platform.
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Ulceration of the Small and Large Bowel Mucosain Resection Specimens of Cystic Fibrosis Patients with Fibrosing Colonopathy
International Journal of Toxicology, 1998Co-Authors: C.l. Lannon, S. A. Hinchliffe, J. D. Pope, L.m. Ball, D Van VelzenAbstract:Fibrosing Colonopathy (FC), observed in cystic fibrosis patients taking high-strength pancreatic enzyme preparations, is characterized by progressive obstruction of the ascending colon, with long-segment fusiform stenosis due to the deposition of submucosal fibrous tissue. The pathogenesis is uncertain, although direct toxic damage to the colonic mucosa by a constituent of such preparations has been proposed as an explanation. Mucosal defects and rectal bleeding have been observed by colonoscopy in cystic fibrosis patients at risk for and with evident FC. In a quantitative, observational study, mucosal defects were studied in six ileo-cecal resection specimens with FC confirmed by three independent pathologists' review. Representative areas (2.5-cm-long segments) were taken of terminal ileum, cecal colon, and ascending colon both at the site of most severe stenosis and at the most distal ascending colon site available; after processing with paraffin, the areas were serially sectioned at 500-μm intervals f...
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Mucosal ulceration in the pathogenesis of Fibrosing Colonopathy of pediatric CF patients related to the use of high-strength enzyme preparations
1997Co-Authors: S. A. Hinchliffe, C. V. Howard, Rosalind L. Smyth, J Pope, D Van VelzenAbstract:The pathogenesis of recently described Fibrosing Colonopathy (FC) recognized in a small proportion of pediatrie cystic fibrosis patients treated with novel high-strength enzyme preparations is as yet unclear. Assessment of colonie mucosa in the 14 cases classified as FC in the United Kingdom national epidemiological study revealed sharply defined limited areas of mucosal defects suggestive of (recent) reepithelialization. Although superficial, nonspecific ulcerations have been described in nonassociated chronic inflammatory bowel disease, these lesions had as yet not been systematically studied in FC patients. The aim of the study was to define the presence and extent of focal mucosal change in the terminal ileum and colon of FC patients. Six ileocecal resection specimens of FC (confirmed by independent pathologist' review) were used for the study. Patients were 2-13 years of age at diagnosis. Two-centimeter segments of terminal ileum, cecum, colon at site of stenosis, and poststenotic ascending colon were serially sliced at 2.5 mm thick and routinely processed to paraffin. Semiserial 5-jlm paraffin sections at 500-um intervals were routinely counted and stained with H&E. Using low magnification, each section was assessed for areas of mucosal change and diagrams representing the mucosa were constructed. From these images, the fraction of surface area affected by mucosal defects was calculated using point scoring and the mean area of the ulcers for each area was calculated from the individual ulcer area as measured by point scoring technique. Surface area ulceration in various states of repair was noted in all colon 3 areas of all six patients. Terminal ileum defects were found in only two out of six patients, mean area 4.5 mm , occupying less than 3% of the surface. Cecal ulcers occupied between 5 and 11% of the surface area, mean ulcer area 4.4 mm (range 2-7 mm ). The highest values were found in the most severely stenosed segments, where ulcers occupied 8-43% of the surface and had a mean size of 2.5 mm (range 1-7 mm ).The poststenotic ascending colon showed 7-19% of the area affected and ulcers had a mean size of 3.7 mm2 (3-9 mm2). Mucosal ulceration in various stages of reepithelialization is found consistently throughout the colon of FC patients. The terminal ileum is affected in only a fraction of patients and when found to a much lesser degree. The role of these mucosal defects in the pathogenesis of FC requires urgent further research. Copyright © 1997 Taylor & Francis.
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Small and large bowel surface area related to body weight and age related to the pathogenesis of Fibrosing Colonopathy in pédiatrie patients
Pediatric Pathology & Laboratory Medicine, 1997Co-Authors: S. A. Hinchliffe, C. V. Howard, Rosalind L. Smyth, J Pope, D Van VelzenAbstract:Fibrosing Colonopathy (FC), recently described in children with cystic fibrosis taking novel high-strength pancreatic enzyme supplements, is of uncertain pathogenesis, although direct damage to the colonie mucosa by a constituent of such preparations is one possible explanation. The strict limitation of the condition to pediatrie age group patients is not explained under such a model of local toxicity. The mucosal concentration of a toxic component of the preparations is a function of total mucosal surface area. However, dosing is based on body weight and does not take into account the possibility of age-related changes in bowel surface area proportional to body weight. The presence of such a relationship might explain the age distribution of FC. At present, this information is not available in the literature. The aim of the study was to determine the relationship between small and large bowel surface area and age/body weight in man. One hundred fifty-four consecutive pediatrie and adult postmortem examinations of patients without history or evidence of bowel disease or congenital malformation were included in the study (83 males, 71 females; age 0-40 years). At autopsy the postduodenal small bowel and large bowel (cecum to rectum inclusive) were removed from the body and their lengths measured separately. Specimens were then opened longitudinally and the mucosal width was determined at 10 systematically random locations distributed equidistantly throughout their length. For each case the mean mucosal widths of small and large bowels were calculated and multiplied by their respective lengths to determine the total mucosal surface areas. Division by body weight gave the surface area/body weight ratio (SA/BW ratio) of small and large bowels. The SA/BW ratio of the small bowel does not differ significantly between birth and 40 years (mean 30.7 cm /kg, range 17.9-52.7 cm /kg). In marked contrast, the SA/BW ratio for the large bowel increases significantly during teenage years from a stable mean of 5.7 cm /kg (age 0-12 years) to41.0cm2/kg (age 19.40years) (P< .001 ). The SA/BW ratio for the large bowel is significantly less than that for the small bowel between the ages of 0 and 14 years (P< .0005). There is no significant relationship between sex and SA/BW ratio for either small or large bowels. Results suggest that in children the concentration of any potential toxin at the colonie mucosa may be five times that in the small bowel. Similarly, for the same dose per unit body weight, the concentration in a child's colon may be seven times that in an adult. We believe these results provide an explanation for the restriction of Fibrosing bowel disease in cystic fibrosis to the colon of children and support a hypothesis of local toxiciry for its pathogenesis. Copyright © 1997 Taylor & Francis.
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Fibrosing Colonopathy in cystic fibrosis: results of a case-control study
Lancet (London England), 1995Co-Authors: Rosalind L. Smyth, Una O'hea, E Burrows, Deborah Ashby, P.a. Lewis, D Van Velzen, J.a. DodgeAbstract:Abstract Summary Fibrosing Colonopathy was first described in cystic fibrosis (CF) children in 1994. We have done a nested case-control study to identify possible associations with this condition. A case ascertainment within the UK CF population to identify any cases that occurred between January, 1984, and April, 1994, found 14 cases, all under 14 years and confirmed by independent histopathological review. All had presented since April, 1993; 12 were boys and six had received some or all of their care in Liverpool. Each case was matched, by date of birth, with four controls from the UK CF Registry. Information was obtained about cases and controls from their case records and by a structured interview with the families. In the 12 months before surgery, there was an association between the occurrence of Fibrosing Colonopathy and use of high-strength pancreatic enzyme preparations. This association was dose related. Odds ratio per extra 1000 high-strength capsules was 1·45 (95% Cl 1·14-1·84). For use of protease, the odds ratio per million extra units per kg was 1·55 (1·19-2·03). For usage of individual high-strength products at any time during the 12 months before surgery some differences were observed; for Creon 25000 the odds ratio was 0·38 (0·10-1·42), for Nutrizym 22 43·4 (2·51-751), and for Pancrease HL 8·4 (1·95-36·1). These last two confidence intervals are extremely wide and compatible with these two products having the same odds ratios. Laxative use was independently predictive (odds ratio 2·42 [1·20–4·94]). We conclude that there is a dose-related association between high-strenght pancreatic enzyme preparations and Fibrosing Colonopathy.
John D. Lloyd-still - One of the best experts on this subject based on the ideXlab platform.
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Indomethacin and Pancreatic Enzymes Synergistically Damage Intestine of Rats
Digestive diseases and sciences, 1998Co-Authors: Robert E. Kimura, V Arango, John D. Lloyd-stillAbstract:The use of high-dose pancreatic enzymes by patients with cystic fibrosis was associated with the development of Fibrosing Colonopathy. Preliminary studies indicated that the infusion of high-dose pancreatic enzymes alone did not cause intestinal damage. We hypothesized that cystic fibrosis patients that developed Fibrosing Colonopathy had increased intestinal permeability. Our goal was to develop a rat model for pancreatic enzyme-induced Fibrosing Colonopathy by increasing intestinal permeability with the use of indomethacin. Pancreatic enzymes, 150,000 units/kg/day, and indomethacin, 3 mg/kg/day, alone and in combination were administered via duodenal catheter to rats for 10 days. Indomethacin and pancreatic enzymes caused intestinal damage, resulting in significant increases in the total number of ulcers (P < 0.007), the number of severe ulcers (P < 0.003), and ulcers in the cecum and colon (P < 0.0007). We conclude that the combination of indomethacin and pancreatic enzymes acts synergistically to cause damage to the intestine.
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High-Dose Pancreatic-Enzyme Supplements and Fibrosing Colonopathy in Children with Cystic Fibrosis
The New England journal of medicine, 1997Co-Authors: Stacey C. Fitzsimmons, Greg A. Burkhart, Drucy Borowitz, Richard J. Grand, Thomas Hammerstrom, Peter R. Durie, John D. Lloyd-still, Albert B. LowenfelsAbstract: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...
C. V. Howard - One of the best experts on this subject based on the ideXlab platform.
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Mucosal ulceration in the pathogenesis of Fibrosing Colonopathy of pediatric CF patients related to the use of high-strength enzyme preparations
1997Co-Authors: Hinchliffe S, C. V. Howard, Pope J, Rl Smyth, Van Velzen DAbstract:The pathogenesis of recently described Fibrosing Colonopathy (FC) recognized in a small proportion of pédiatrie cystic fibrosis patients treated with novel high-strength enzyme preparations is as yet unclear. Assessment of colonie mucosa in the 14 cases classified as FC in the United Kingdom national epidemiological study revealed sharply defined limited areas of mucosal defects suggestive of (recent) reepithelialization. Although superficial, nonspecific ulcérations have been described in nonassociated chronic inflammatory bowel disease, these lesions had as yet not been systematically studied in FC patients. The aim of the study was to define the presence and extent of focal mucosal change in the terminal ileum and colon of FC patients. Six ileocecal resection specimens of FC (confirmed by independent pathologist' review) were used for the study. Patients were 2-13 years of age at diagnosis. Two-centimeter segments of terminal ileum, cecum, colon at site of stenosis, and poststenotic ascending colon were serially sliced at 2.5 mm thick and routinely processed to paraffin. Semiserial 5-jlm paraffin sections at 500-um intervals were routinely counted and stained with H&E. Using low magnification, each section was assessed for areas of mucosal change and diagrams representing the mucosa were constructed. From these images, the fraction of surface area affected by mucosal defects was calculated using point scoring and the mean area of the ulcers for each area was calculated from the individual ulcer area as measured by point scoring technique. Surface area ulcération in various states of repair was noted in all colon 3 areas of all six patients. Terminal ileum defects were found in only two out of six patients, mean area 4.5 mm , occupying less than 3% of the surface. Cecal ulcers occupied between 5 and 11% of the surface area, mean ulcer area 4.4 mm (range 2-7 mm ). The highest values were found in the most severely stenosed segments, where ulcers occupied 8-43% of the surface and had a mean size of 2.5 mm (range 1-7 mm ).The poststenotic ascending colon showed 7-19% of the area affected and ulcers had a mean size of 3.7 mm2 (3-9 mm2). Mucosal ulcération in various stages of reepithelialization is found consistently throughout the colon of FC patients. The terminal ileum is affected in only a fraction of patients and when found to a much lesser degree. The role of these mucosal defects in the pathogenesis of FC requires urgent further research. Copyright © 1997 Taylor & Francis
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Mucosal ulceration in the pathogenesis of Fibrosing Colonopathy of pediatric CF patients related to the use of high-strength enzyme preparations
1997Co-Authors: S. A. Hinchliffe, C. V. Howard, Rosalind L. Smyth, J Pope, D Van VelzenAbstract:The pathogenesis of recently described Fibrosing Colonopathy (FC) recognized in a small proportion of pediatrie cystic fibrosis patients treated with novel high-strength enzyme preparations is as yet unclear. Assessment of colonie mucosa in the 14 cases classified as FC in the United Kingdom national epidemiological study revealed sharply defined limited areas of mucosal defects suggestive of (recent) reepithelialization. Although superficial, nonspecific ulcerations have been described in nonassociated chronic inflammatory bowel disease, these lesions had as yet not been systematically studied in FC patients. The aim of the study was to define the presence and extent of focal mucosal change in the terminal ileum and colon of FC patients. Six ileocecal resection specimens of FC (confirmed by independent pathologist' review) were used for the study. Patients were 2-13 years of age at diagnosis. Two-centimeter segments of terminal ileum, cecum, colon at site of stenosis, and poststenotic ascending colon were serially sliced at 2.5 mm thick and routinely processed to paraffin. Semiserial 5-jlm paraffin sections at 500-um intervals were routinely counted and stained with H&E. Using low magnification, each section was assessed for areas of mucosal change and diagrams representing the mucosa were constructed. From these images, the fraction of surface area affected by mucosal defects was calculated using point scoring and the mean area of the ulcers for each area was calculated from the individual ulcer area as measured by point scoring technique. Surface area ulceration in various states of repair was noted in all colon 3 areas of all six patients. Terminal ileum defects were found in only two out of six patients, mean area 4.5 mm , occupying less than 3% of the surface. Cecal ulcers occupied between 5 and 11% of the surface area, mean ulcer area 4.4 mm (range 2-7 mm ). The highest values were found in the most severely stenosed segments, where ulcers occupied 8-43% of the surface and had a mean size of 2.5 mm (range 1-7 mm ).The poststenotic ascending colon showed 7-19% of the area affected and ulcers had a mean size of 3.7 mm2 (3-9 mm2). Mucosal ulceration in various stages of reepithelialization is found consistently throughout the colon of FC patients. The terminal ileum is affected in only a fraction of patients and when found to a much lesser degree. The role of these mucosal defects in the pathogenesis of FC requires urgent further research. Copyright © 1997 Taylor & Francis.
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Small and large bowel surface area related to body weight and age related to the pathogenesis of Fibrosing Colonopathy in pédiatrie patients
Pediatric Pathology & Laboratory Medicine, 1997Co-Authors: S. A. Hinchliffe, C. V. Howard, Rosalind L. Smyth, J Pope, D Van VelzenAbstract:Fibrosing Colonopathy (FC), recently described in children with cystic fibrosis taking novel high-strength pancreatic enzyme supplements, is of uncertain pathogenesis, although direct damage to the colonie mucosa by a constituent of such preparations is one possible explanation. The strict limitation of the condition to pediatrie age group patients is not explained under such a model of local toxicity. The mucosal concentration of a toxic component of the preparations is a function of total mucosal surface area. However, dosing is based on body weight and does not take into account the possibility of age-related changes in bowel surface area proportional to body weight. The presence of such a relationship might explain the age distribution of FC. At present, this information is not available in the literature. The aim of the study was to determine the relationship between small and large bowel surface area and age/body weight in man. One hundred fifty-four consecutive pediatrie and adult postmortem examinations of patients without history or evidence of bowel disease or congenital malformation were included in the study (83 males, 71 females; age 0-40 years). At autopsy the postduodenal small bowel and large bowel (cecum to rectum inclusive) were removed from the body and their lengths measured separately. Specimens were then opened longitudinally and the mucosal width was determined at 10 systematically random locations distributed equidistantly throughout their length. For each case the mean mucosal widths of small and large bowels were calculated and multiplied by their respective lengths to determine the total mucosal surface areas. Division by body weight gave the surface area/body weight ratio (SA/BW ratio) of small and large bowels. The SA/BW ratio of the small bowel does not differ significantly between birth and 40 years (mean 30.7 cm /kg, range 17.9-52.7 cm /kg). In marked contrast, the SA/BW ratio for the large bowel increases significantly during teenage years from a stable mean of 5.7 cm /kg (age 0-12 years) to41.0cm2/kg (age 19.40years) (P< .001 ). The SA/BW ratio for the large bowel is significantly less than that for the small bowel between the ages of 0 and 14 years (P< .0005). There is no significant relationship between sex and SA/BW ratio for either small or large bowels. Results suggest that in children the concentration of any potential toxin at the colonie mucosa may be five times that in the small bowel. Similarly, for the same dose per unit body weight, the concentration in a child's colon may be seven times that in an adult. We believe these results provide an explanation for the restriction of Fibrosing bowel disease in cystic fibrosis to the colon of children and support a hypothesis of local toxiciry for its pathogenesis. Copyright © 1997 Taylor & Francis.
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Small and large bowel surface area related to body weight and age related to the pathogenesis of Fibrosing Colonopathy in pédiatrie patients
1997Co-Authors: Hinchliffe S, C. V. Howard, Pope J, Rl Smyth, Van Velzen DAbstract:Fibrosing Colonopathy (FC), recently described in children with cystic fibrosis taking novel high-strength pancreatic enzyme supplements, is of uncertain pathogenesis, although direct damage to the colonie mucosa by a constituent of such preparations is one possible explanation. The strict limitation of the condition to pédiatrie age group patients is not explained under such a model of local toxicity. The mucosal concentration of a toxic component of the preparations is a function of total mucosal surface area. However, dosing is based on body weight and does not take into account the possibility of age-related changes in bowel surface area proportional to body weight. The presence of such a relationship might explain the age distribution of FC. At present, this information is not available in the literature. The aim of the study was to determine the relationship between small and large bowel surface area and age/body weight in man. One hundred fifty-four consecutive pédiatrie and adult postmortem examinations of patients without history or evidence of bowel disease or congenital malformation were included in the study (83 males, 71 females; age 0-40 years). At autopsy the postduodenal small bowel and large bowel (cecum to rectum inclusive) were removed from the body and their lengths measured separately. Specimens were then opened longitudinally and the mucosal width was determined at 10 systematically random locations distributed equidistantly throughout their length. For each case the mean mucosal widths of small and large bowels were calculated and multiplied by their respective lengths to determine the total mucosal surface areas. Division by body weight gave the surface area/body weight ratio (SA/BW ratio) of small and large bowels. The SA/BW ratio of the small bowel does not differ significantly between birth and 40 years (mean 30.7 cm /kg, range 17.9-52.7 cm /kg). In marked contrast, the SA/BW ratio for the large bowel increases significantly during teenage years from a stable mean of 5.7 cm /kg (age 0-12 years) to41.0cm2/kg (age 19.40years) (P< .001 ). The SA/BW ratio for the large bowel is significantly less than that for the small bowel between the ages of 0 and 14 years (P< .0005). There is no significant relationship between sex and SA/BW ratio for either small or large bowels. Results suggest that in children the concentration of any potential toxin at the colonie mucosa may be five times that in the small bowel. Similarly, for the same dose per unit body weight, the concentration in a child's colon may be seven times that in an adult. We believe these results provide an explanation for the restriction of Fibrosing bowel disease in cystic fibrosis to the colon of children and support a hypothesis of local toxiciry for its pathogenesis. Copyright © 1997 Taylor & Francis
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Comparative and experimental pathology of Fibrosing Colonopathy.
Postgraduate medical journal, 1996Co-Authors: Van Velzen D, Southgate A, C. V. HowardAbstract:Although the occurrence of Fibrosing Colonopathy is temporally associated with the introduction of high-strength pancreatic enzyme supplements, its pathogenesis remains uncertain. The UK case-control study showed Fibrosing Colonopathy to be associated with high doses of high-strength pancreatic enzyme supplements and with a group of brands which occupy only 30% of the market. Two alternative hypotheses were proposed to explain the aetiology of Fibrosing Colonopathy: exposure to high levels of enzymes or to as yet unidentified components of the formulation. Comparison of the anatomical pathology of Fibrosing Colonopathy with that of previously encountered forms of obstructive gastrointestinal pathology, such as stricturing lesions due to potassium chloride preparations and nonsteroidal anti-inflammatory drugs, confirmed it to be a previously unencountered, long-segment lesion of the colon. Thus the use of the descriptive term 'stricture' is a misnomer leading to much clinical confusion when discussing obstructive bowel pathology in cystic fibrosis patients. Gavage studies in the rat with one of the two monomers (ethyl acrylate) forming the methacrylic acid copolymer (Eudragit L30D55) used for the enteric coating of the high-strength pancreatic enzyme supplements, have shown pathology comparable to Fibrosing Colonopathy. These findings prompted a series of exploratory studies in adolescent pigs. After seven days caecal gavage of Eudragit L30D55 at doses of 10, 50 or 500 mg/kg/day (comparable to human intake), extensive Fibrosing Colonopathy-like changes, inclusive of dense submucosal fibrosis, were noted at all dose levels in seven out of nine animals. Similar studies of the monomer components of the Eudragit L30D55 copolymer, at dose levels of 0.015 to 50 mg/kg/day, representing possible residues in Eudragit L30D55, did not produce comparable changes. The conclusion is that, although the precise mechanisms have not been elucidated, the role of enteric coatings containing Eudragit L30D55 in the pathogenesis of Fibrosing Colonopathy requires urgent further study.