Marc Peeters

Controlled trial of metronidazole treatment for prevention of crohn's recurrence after ileal resection☆

BACKGROUND/AIMSnNew lesions recur within weeks to months after ileal resection and ileocolonic anastomosis for Crohns ileitis. A double-blind controlled trial was performed using metronidazole to prevent recurrence after ileal resection.nnnMETHODSnSixty patients who underwent curative ileal resection and primary anastomosis were included within 1 week after surgery. Thirty patients received metronidazole (20 mg/kg body wt) daily for 3 months, and 30 patients received placebo. Treatment was then discontinued. Nine patients dropped out during treatment, 7 in the metronidazole group and 2 in the placebo arm.nnnRESULTSnAt 12 weeks, 21 of 28 patients (75%) in the placebo group had recurrent lesions in the neoterminal ileum as compared with 12 of 23 patients (52%) in the metronidazole group (P = 0.09). The incidence of severe endoscopic recurrence was significantly reduced by metronidazole (3 of 23; 13%) as compared with placebo (12 of 28; 43%; P = 0.02). Patients in the metronidazole arm had more frequent side effects. Metronidazole therapy statistically reduced the clinical recurrence rates at 1 year (4% vs. 25%). Reductions at 2 years (26% vs. 43%) and 3 years (30% vs. 50%) were not significant.nnnCONCLUSIONSnMetronidazole therapy for 3 months decreases the severity of early recurrence of Crohns disease in the neoterminal ileum after resection and seems to delay symptomatic recurrence.

Effect of faecal stream diversion on recurrence of Crohn's disease in the neoterminal ileum

Aphthous lesions recur in the neoterminal ileum within the first few months after curative resection of the distal ileum in patients with Crohns disease. These lesions do not originate from microscopic disease that is already present at the time of surgery. To investigate the importance of faecal stream in the pathogenesis of recurrent Crohns lesions, we have studied 5 patients with Crohns disease who had ileal resection. After curative resection and ileocolonic anastomosis, a diverting terminal ileostomy was constructed 25-35 cm proximal to the anastomosis thereby excluding the neoterminal ileum, the anastomosis, and the colon from intestinal transit. After six months of exclusion, endoscopy of the ileocolon was undertaken and biopsy specimens were taken. Transit was then restored. Six months after reanastomosis further biopsy specimens were taken. These patients were compared with a control group of 75 patients with Crohns disease who underwent a one-step ileal resection and ileocolonic anastomosis. None of the 5 patients had endoscopic lesions in the neoterminal ileum after six months of exclusion and biopsies did not show inflammatory changes characteristic of Crohns disease. By contrast, 53 of 75 patients with one-step surgery had endoscopic recurrence in the neoterminal ileum within six months of surgery. All 5 patients had an important recurrence of disease, both endoscopically and histologically, at ileocolonoscopy six months after reanastomosis. Our findings strongly support the view that recurrence of Crohns disease in the neoterminal ileum after curative ileal resection is dependent on faecal stream.

Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease

OBJECTIVES:Correct diagnosis of inflammatory bowel disease (IBD), especially the differentiation between Crohns disease (CD) and ulcerative colitis (UC), is highly important toward treatment and prognosis. Serological markers are noninvasive diagnostic tools that could be of value in differentiating CD from UC, in cases of indeterminate colitis, and in the identification of subgroups in IBD. The aim of this study was to evaluate the diagnostic accuracy of perinuclear antineutrophil cytoplasmic (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) for IBD.METHODS:ASCA and pANCA were studied in a large cohort of consecutive IBD patients (n = 582: 407 CD, 147 UC, and 28 indeterminate colitis), patients with non-IBD diarrheal illnesses (n = 74), and healthy controls (n = 157). An indirect immunofluorescence technique and a standardized ELISA were performed for detection of pANCA and ASCA, respectively.RESULTS:Prevalence of ASCA and pANCA was high in CD patients (59.7%) and UC (49.7%) patients, respectively. Positivity for both markers was significantly lower in healthy and non-IBD controls. Accuracy data (sensitivity, specificity, PPV, and NPV, respectively) for differentiating IBD from controls are as follows: ASCA+: 60% (243/407), 91% (345/378), 88% (243/276), and 68% (345/509); pANCA+: 50% (73/147), 95% (605/638), 69% (73/106), and 89% (605/679); ASCA+/pANCA−: 56% (229/407), 94% (355/378), 91% (229/252), and 67% (355/533); and pANCA+/ASCA−: 44% (65/147), 97% (620/638), 78% (65/83), and 88% (620/702).CONCLUSIONS:Specificity of serological markers for IBD is high, but low sensitivity makes them less useful as diagnostic tests. The combination of tests is probably more powerful, although, clinical subgroups still need to be defined. The usefulness of these markers in indeterminate colitis needs to be studied prospectively.

Anti‐Saccharomyces Cerevisiae antibodies (ASCA), phenotypes of IBD, and intestinal permeability: A study in IBD families

BackgroundSerologic markers anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies with perinuclear staining (pANCA) have been proposed to study the immunopathogenesis of IBD. Their measurement may allow better phenotyping of the disease and the detection of subclinical disease. AimsTo test the hypothesis that serological markers identify an immunologic trait related to disease susceptibility. We also wanted to test the hypothesis that ASCA is a marker related to abnormal tissue permeation by common antigens. MethodsWe studied the prevalence of pANCA and ASCA in a large cohort of sporadic and familial inflammatory bowel diseases and their unaffected relatives and spouses. Kinetics of ASCA was studied and the relationship between ASCA and 51Cr-EDTA intestinal permeation was investigated. ResultsASCA was associated with sporadic Crohns disease (CD) (63%), with Crohns patients belonging to pure CD families (62%) and also with their unaffected family members (21%). pANCA was associated with UC (58%). The prevalence of ASCA in CD patients belonging to mixed families was strikingly low (33%). ASCA was a stable marker throughout the disease and was not related to an increased small intestinal permeability. ConclusionASCA is strongly associated with familial CD in Belgium, and 21% of healthy family members also display the marker. The association is much weaker in patients belonging to mixed families. ASCA is a stable marker and is not a secondary phenomenon due to increased intestinal permeability.

Effect of Long-Term Oral Glutamine Supplements on Small Intestinal Permeability in Patients With Crohn's Disease

BACKGROUNDnGlutamine is a major fuel and an important nitrogen source for the small intestinal cell. It plays a key role in maintaining mucosal cell integrity and gut barrier function. Increased permeability may be a factor in the pathogenesis of Crohns disease and may be an interesting parameter in the follow-up of the disease. Therefore, the aim of this study was to examine whether oral glutamine supplements are able to restore an increased intestinal permeability in patients with Crohns disease.nnnMETHODSnThe inclusion criteria for the study were Crohns disease and a disturbed small intestinal permeability for 51Cr-EDTA. Of 38 patients screened, 18 had an increased permeability (6 hours urinary excretion >1.1% of label recovered in urine). Fourteen patients were included in the study and were randomized to receive either oral glutamine (7 g three times per day; n = 7) or placebo (7 g glycine three times per day; n = 7) in addition to their normal treatment during a 4-week period. The study was performed in a double-blind manner.nnnRESULTSnBaseline permeability (mean +/- SD) was 2.32%+/-0.77% dose in the glutamine group and 2.29%+/-0.67% dose in the placebo group. Permeability did not change significantly after glutamine (3.26%+/-2.15% dose) or after placebo (2.27%+/-1.32% dose). There was no significant effect on plasma glutamine, plasma glutamate, plasma ammonium, Crohns disease activity index, C-reactive protein, or nutritional status.nnnCONCLUSIONSnOral glutamine supplements, in the dose administered, do not seem to restore impaired permeability in patients with Crohns disease.

Helicobacter pylori infection and growth delay in older children.

It is thought that Helicobacter pyloriinfection may influence growth rate in children. The aim of this study was to evaluate the prevalence of H pylori infection in healthy Italian children, and to look for differences in height between infected and non-infected subjects. Two hundred and sixteen children, aged 3 to 14 years, were tested for H pylori infection by13C-urea breath test. Centile values for height were calculated. Composite indices for socioeconomic class and household crowding were also determined. Forty nine of 216 children (22.7%) wereH pylori positive. The prevalence of infection increased with age. Eight of 49 H pylori positive children (16.3%) were below the 25th centile for height, compared with 13 of 167 H pylori negative children (7.8%). This difference became significant in children aged 8.5 to 14 years; in this group (n = 127), eight of 31 infected children (25.8%) were below the 25th centile for height, compared with eight of 96 non-infected children (8.3%). A significant correlation was found between socioeconomic conditions, household crowding, and H pylori status. By using stepwise logistic regression, only the centile value for height was significantly related to H pylori status in older children. Thus H pylori infection was associated with growth delay in older children, poor socioeconomic conditions, and household overcrowding. This finding is consistent with the hypothesis that H pylori infection is one of the environmental factors capable of affecting growth.

Tumour necrosis factor (TNF) gene polymorphism in Crohn's disease (CD): influence on disease behaviour?

Crohns disease (CD) is a multifactorial disease with genetic heterogeneity. TNF‐α plays a key role in the development of the mucosal lesions. The aim of our work was to study a single base pair polymorphism located in the promoter region of TNF gene, in a large population of CD patients with well defined phenotypes. One hundred and ninety‐three patients with CD and 98 ethnically matched controls were studied. The −308 single base pair polymorphism of TNF gene was studied using an allele‐specific polymerase chain reaction. Genotype and allelic frequencies were compared between patients and controls and between subgroups of patients defined by sex, age at diagnosis, familial history, location of disease, type of disease, extra‐intestinal manifestations, and response to steroid treatment. In 29 patients a measure of TNF‐α production by colonic biopsies was performed. The frequency of the allele TNF2 as well as the proportion of carriers of the allele TNF2 were slightly but not significantly lower in CD than in controls (11.9% versus 14.8% and 21.5% versus 27.6%, respectively). A more prominent difference in frequencies of allele TNF2 and in proportions of TNF2 carriers was found when comparing subgroups of patients. The frequency of allele TNF2 was significantly higher in steroid‐dependent than in non‐steroid‐dependent disease (28.1% versus 10.3%; Δu2003=u200317.8%, 95% confidence interval (CI)u2003=u20036.3–29.5%, Pu2003=u20030.0027) and tended to be higher in colonic than in small bowel disease and in fistulizing than in stricturing disease. Furthermore, TNF2 carriers tended to be more frequent in patients with steroid‐dependent than non‐steroid‐dependent disease (43.8% versus 19.3%; Δu2003=u200324.5%, 95% CIu2003=u20033.6–45.4%, Pu2003=u20030.022), in patients with fistulizing than stricturing disease (26.5% versus 9.6%; Δu2003=u200316.9%, 95% CIu2003=u20031.1–32.6%, Pu2003=u20030.036), and in patients with colonic than small bowel disease (26.5% versus 11.1%; Δu2003=u200315.4%, 95% CIu2003=u2003−0.8–31.6%, Pu2003=u20030.063). Finally, patients carrying at least one copy of allele 2 were found to produce slightly more TNF‐α at the colonic level. The −308 TNF gene polymorphism may have a slight influence on the behaviour of CD. The carriage of allele 2 may favour steroid‐dependent disease and to a lesser extent fistulizing and colonic disease, possibly secondary to a more intense TNF‐α‐driven inflammatory reaction at the mucosal level.

Comparison of total and compartmental gastric emptying and antral motility between healthy men and women

Abstract. There is increasing evidence of gender-related differences in gastric emptying. The purpose of this study was first, to confirm the difference in gastric emptying for both solid and liquid test meals between healthy men and women, and secondly, to investigate the origin of this difference by studying regional gastric emptying and antral motility. A standard gastric emptying test with additional compartmental (proximal and distal) evaluation and dynamic imaging of the antrum was performed in 20 healthy women studied during the first 10 days of the menstrual cycle, and in 31 healthy age-matched men. In concordance with previous reports, women had a longer half-emptying time for solids as compared to men (86.2±5.1 vs 52.2±2.9 min, P<0.05). In our observations this seemed to be related to a significantly prolonged lag phase and a significant decrease in terminal slope. Dynamical antral scintigraphy did not show a significant difference. The distribution of the test meal within the stomach (proximal vs distal) showed more early proximal retention in women as compared to men. The terminal slope of the distal somach was significantly lower in women. We did not observe a significant difference in gastric emptying of the liquid test meal between men and women. Gastric emptying of solids is significantly slower in healthy women as compared to men. These findings emphasise the importance of using different normal values for clinical and research purposes in gastric emptying scintigraphy in men and women. The difference could not be explained by antral motility alone. Increased proximal retention and a lower terminal emptying rate in women are observations to be further investigated.

Evaluation of small bowel transit for solid and liquid test meal in healthy men and women

Abstract. Evaluation of severe functional gastrointestinal motility disorders requires an investigation of the entire gastrointestinal tract. This should be possible with a single radionuclide imaging study. The purpose of this study was (1) to define normal values of small-bowel transit in men and women and (2) to assess a possible difference between gender or test meal, since it has been shown that women have slower gastric emptying than men, and gastric emptying of solids is slower than liquids. A standard gastric-emptying test for a solid (technetium-99m sulphur colloid, 230 Kcal) and liquid (indium-111 DTPA water) test meal was performed in 12 healthy male and 12 healthy female volunteers. After 135 min, the volunteer was placed in the supine position for static imaging of the abdomen every 15 min for 6 h. Decay and crossover-corrected geometric mean gastric-emptying data were fit to a modified power exponential function to determine the 10% stomach emptying time for solids and liquids separately. An ROI was drawn around the caecum and ascending colon to determine the arrival time of at least 10% of the solid and liquid test meal. Ten percent small-bowel transit time (10%SBTT) and orocaecal transit time (OCTT) were calculated.The OCTT for males and females, respectively for solids and liquids, are 294.6±18.8; 301.3±24.5; 294.6±18.8 and 301.3±24.5 min. The 10%SBTT for males and females, respectively for solids and liquids, are 280.3±18.4; 280.6±24.0; 288.2±18.9 and 297.4±24.4 (mean±SEM) min. We observed a simultaneous transfer of solids and liquids from the terminal ileum to caecum (correlation coefficient 0.90). There is no statistically significant difference in SBTT between gender or solids and liquids. In contrast to the gastric-emptying time, the SBTT of solids and liquids were not significantly different nor was a gender difference found. Determination of the OCTT seems to be the simplest and most accurate approach to measure SBTT. Since ileocaecal transfer occurs as a bolus phenomenon, a 111In-labelled test meal can also be used for the determination of colon transit in a single imaging study protocol.

INCREASED PERMEABILITY OF MACROSCOPICALLY NORMAL SMALL BOWEL IN CROHN'S DISEASE

To investigate permeability alterations of the macroscopically normal jejunum in Crohns disease, the permeation of two probes was measured during perfusion of an isolated jejunal segment. The data were compared with the results obtained by the standard per oral test in the same patients. Test probes were PEG-400 and [51Cr]EDTA. Ten normal individuals, 12 patients with Crohns ileitis or ileocolitis, and seven patients with isolated Crohns colitis all with normal jejunum on x-ray series were studied. Upon perfusion of the proximal small bowel, the 3-hr [51Cr]EDTA excretion was significantly increased in ileitis patients (P=0.023) as compared to normals. The excretion exceeded the highest value of normals in eight of 12 ileitis patients. The excretion in Crohns colitis patients was not significantly increased (P=0.24) and abnormal excretion was found only in one of the Crohns colitis patients. PEG-400 permeation during perfusion did not differentiate between the groups, but five of the seven patients with isolated Crohns colitis had PEG-400 excretion exceeding the highest value in normals. Overall, 13 of the 19 patients had increased permeation of one of the two probes through jejunal mucosa during perfusion. These data suggest that the permeability is increased in the majority of patients even in segments that seem normal on x-ray.