R. Caprilli

European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations

This third section of the European Crohn’s and Colitis Organisation (ECCO) Consensus on the management of Crohn’s disease concerns postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy. The first section on definitions and diagnosis reports on the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn’s disease. The second section on current management addresses treatment of active disease, maintenance of medically induced remission, and surgery of Crohn’s disease.

Rectal irrigation with short-chain fatty acids for distal ulcerative colitis. Preliminary report.

Colon cells from patients with ulcerative colitis utilize short-chain fatty acids inefficiently and may be exposed to decreased concentrations of these compounds. To test whether irrigation of the inflamed mucosa with short-chain fatty acids is useful, we conducted a six-week preliminary trial in 12 patients with distal colitis. Each patient used twice daily rectal irrigations with 100 ml of a solution containing acetate (80 mM), propionate (30 mM), and butyrate (40 mM). Two patients stopped at three weeks, one because of no improvement and the other because of complete resolution of symptoms. Of the 10 who completed the trial, nine were judged to be at least much improved and showed a change in a mean disease activity index score from 7.9±0.3 (se) to 1.8±0.6 (se) (P≤0.002) and in a mucosal histology score from 7.7±0.7 (se) to 2.6±0.7 (se) (P≤0.002). Thus, ulcerative colitis patients appear to benefit from increased contact with or higher than usual levels of these critical energy substrates.

Dextran Sulfate Sodium (DSS) Colitis in Rats (Clinical, Structural, and Ultrastructural Aspects)

Aim of this study was to assess the structural,ultrastructural, immunohistochemical, and clinicalaspects in Sprague-Dawley rats with dextrane sulfatesodium (DSS)-induced colitis. Colitis was induced in Sprague-Dawley rats by seven days of DSSoral administration followed by seven days of tap wateronly (for one, two and three cycles). Controls were fedwith water only. Segments of proximal, mid-, and distal colon of each animal were adequatelyprepared for light and scanning electron microscopeobservations. The severity of the lesions was scoredhistologically. For immunohistochemical study, acocktail of S-100, NSE, and antineurofilament antibodieswas used. Symptoms such as weight, feces consistency,diarrhea, hematochezia were recorded daily. From aclinical point of view symptoms appeared significantly later after the first cycle than after thesecond and third cycles and lasted significantly longerin the second and third cycles. Treated rats showed aslower weight gain rate by 20% compared to controls, and the whole colon length appeared to besignificantly shorter after colitis induction comparedto controls. Structural observations by light microscopyshowed prominent involvement of the distal colon. Immunohistochemical study of both submucosaland myoenteric nerve plexuses was similar to controls.Scanning electron microscope observations of the colonicmucosal surface in colitis rats showed a complete subversion of its architecture, characterizedby dilatations of gland crypt openings, dropout ofgoblet cells, and inhomogeneous distribution or lack ofmicrovilli. These were most evident after the third cycle. In conclusion, experimental DSS colitisin SD rats appeared to be highly reproducible and sharedmost features with human UC, not only from a structuraland clinical but also from an ultrastructural point of view.

Reversal of Iron Deficiency Anemia after Helicobacter pylori Eradication in Patients with Asymptomatic Gastritis

Standard care for men and postmenopausal women with iron deficiency anemia is use of gastrointestinal evaluation to exclude gastrointestinal tract abnormality (1, 2). Nevertheless, even when the gastrointestinal tract is investigated thoroughly, a large proportion of patients (around 30%) remain without a diagnosis (2, 3). Recent epidemiologic studies have suggested an association between Helicobacter pylori infection and iron deficiency (4, 5). Infection with H. pylori is recognized as a major risk factor in peptic ulcer disease and gastric cancer, in which lesions are likely to bleed either overtly or in an occult manner, eventually leading to iron deficiency anemia. However, most people infected with H. pylori only have chronic gastritis that is not associated with gastrointestinal bleeding or with any other specific disease (6). It has been suggested that infection with H. pylori may lead to iron deficiency or iron deficiency anemia by impairing iron uptake or increasing iron demand (4). Reversal of iron deficiency anemia after successful eradication of H. pylori was recently observed in children (7, 8) and in a young adult (9). We performed a prospective open study to verify the effects of eradication of H. pylori infection on iron deficiency anemia in patients with H. pylori-associated gastritis. Methods Patients Patients were observed from September 1994 to December 1997. A total of 189 consecutive adult outpatients who were older than 20 years of age and had iron deficiency anemia (158 women and 31 men; median age, 47 years [range, 20 to 79 years]) were referred to our gastroenterology department from the hematology department. Iron-deficiency anemia was defined as a hemoglobin concentration less than 14 g/L for men and less than 12 g/L for women, a mean corpuscular volume less than 80 fL, and a serum ferritin level less than 30 g/L (3). Outpatients with an obvious cause of blood loss, such as a heavy menstrual period (cycles>6 days), epistaxis, active gastrointestinal hemorrhage, or evidence of fecal occult blood positivity, were excluded from the study. Other exclusion criteria were gastrointestinal or hematologic cancer at the time of observation, chronic renal failure, severe cardiopulmonary disease, reported or suspected pica, hemolysis, aplastic anemia or thalassemia, alcoholism or liver cirrhosis, and pregnancy. After this selection, patients who were taking nonsteroidal anti-inflammatory drugs; had had gastric surgery; or had atrophic body gastritis and celiac disease, as described elsewhere (3), were excluded from the study. An iron-poor diet as a cause of iron deficiency anemia was excluded by a hospital dietitian (3). A double-contrast barium enema or colonoscopy plus radiographic examination of the small bowel, or Meckel scintigraphy, were also carried out if indicated. Interventions Patients were treated for 2 weeks with omeprazole, 40 mg, in the morning; amoxicillin, 1g; and metronidazole, 250 mg three times daily after meals, for the first week. Patients were also instructed to discontinue any iron replacement therapy, including over-the-counter iron-containing medication. A clinical evaluation was performed 3 months after eradication therapy to check for clinical signs of anemia. Two follow-up visits at 6 and 12 months were planned. At each visit, a complete blood count was done and ferritin levels were measured. Baseline and 12-month transferrin saturation indexes were also calculated. The 6-month follow-up examination included endoscopy with biopsy to evaluate H. pylori eradication. Patients were considered cured of H. pylori infection if both rapid urease testing and histologic examination of the gastric antral and body biopsy samples were negative. Successful eradication therapy for iron deficiency anemia was defined as no need for iron replacement therapy, recovery from anemia, or both. All patients gave full informed consent to participate the study, which was approved by the local ethical committee. Measurements History of anemia, expressed as length of time from first laboratory diagnosis of iron deficiency anemia to referral to the gastroenterology department, was assessed. Serum ferritin levels were measured by using commercial kits (Ciba-Corning Diagnostic Corp., Milan, Italy) (3). Hemoglobin concentrations and mean corpuscular volume were determined by an automated Coulter counter (Technicon H1, Bayer Corp., Tarrytown, New York) (3). Serum transferrin levels were measured by using a commercial kit (Beckman Analytical, Milan, Italy) (10). Serum iron levels were measured and the transferrin saturation index (normal value, 16% to 45%) was calculated as described elsewhere (10). Patients underwent gastroscopy with gastric antral (n=3) or body (n=3) biopsy. One sample was tested by using a rapid urease test, and the others were examined by conventional histology (3, 9). Duodenal biopsy specimens were also obtained to exclude celiac disease. The pathologist was unaware of clinical and endoscopic data. Gastritis status was described according to the Updated Sydney System classification (8). Helicobacter pylori status was considered positive when the organism was detected on histologic examination, by rapid urease testing, or both. Statistical Analysis Data are expressed as the mean ( SE) or median (range) as appropriate and were analyzed by using the t-test for paired data. Subgroups (percentages of patients) were compared by using the McNemar test. A P value less than 0.05 was considered statistically significant. Role of the Funding Sources Our funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Of the 189 patients referred to our gastroenterology department, 30 (15.9%) had iron deficiency anemia: 4 men and 26 women (of whom 3 were postmenopausal) with a median age of 35.5 years (range, 20 to 65 years). In these patients, H. pylori-associated gastritis was the only pathologic finding. Gastroscopy did not reveal any sign of current or past mucosal erosion or ulcer disease. All patients had a suboptimal response to oral iron therapy; they needed continuous or intermittent oral iron treatment to prevent the decrease of hemoglobin levels. All patients denied having any specific gastrointestinal symptom or having used antisecretory drugs. Occasional, nonpersistent, mild dyspeptic symptoms were considered nonspecific. Anamnestic interview and evaluation of previous medical records documented moderate to severe iron deficiency anemia in all patients (hemoglobin level, 9.5 0.25 g/L; mean corpuscular volume, 69 1.15 fL; and serum ferritin level, 6.2 0.8 g/L) associated with clear clinical signs of anemia, such as fatigue, pallor, and decreased exercise capacity. Median history of anemia and of oral iron therapy in these patients was 4.8 years (range, 2 to 20 years). All patients underwent an eradication regimen. At the 3-month clinical evaluation, no patients reported anemia-related symptoms. Twenty-eight patients underwent endoscopy at 6 months to verify H. pylori eradication. Two female patients (27 and 36 years of age) declined further follow-up because they were in good general health. Helicobacter pylori infection was cured in 25 patients (89.3% [95% CI, 72% to 98%]); at this point, one female 31-year-old patient was excluded from further follow-up because she had developed heavy menstrual periods due to a uterine myoma that was not present at the initial diagnosis. Thus, 24 patients (3 men and 21 women; median age, 35.7 years [range, 20 to 65 years]) in whom H. pylori infection was cured and 3 patients (1 man 21 years of age and 2 women 22 and 37 years of age) in whom H. pylori infection was not cured were eligible for evaluation. Effects of Helicobacter pylori Eradication on Iron Deficiency Anemia At 6 months of follow-up, 18 of 24 (75%) patients recovered from anemia (P<0.001) and had a significant increase in the hemoglobin concentration, mean corpuscular volume, and ferritin level (Table). Table. Hematologic Data from 24 Patients with Iron Deficiency Anemia At 12 months of follow-up, 4 more patients (22 of 24 [91.7%]) showed recovery from anemia without resuming iron supplementation. The mean values of all measurements obtained were similar to those seen at the 6-month evaluation (Table). Even though ferritin levels returned to normal in only 4 patients at the 12-month follow-up visit, we observed a significant increase of more than 300% over baseline values (5.7 0.7 g/L compared with 24.1 5.0 g/L [P=0.0018]; mean increase, 18.4 g/L [CI, 8.08 to 29.44 g/L]). Mean transferrin saturation index also significantly increased from baseline (from 5.5% 0.8% to 18.7% 1.8% [P<0.001]; mean increase, 13.2 percentage points [CI, 8.92 to 17.46 percentage points]), even though values in 5 patients were still below the normal range. Eight patients were followed for 1 more year. Hemoglobin levels returned to normal in the two patients who were still anemic at the previous 12-month examination. In these patients, ferritin levels further increased from those measured at the 12-month follow-up (23.9 6.7 g/L and 30.5 7.4 g/L [P=0.047]; mean increase, 6.6 g/L [CI, 0.5 to 12.6 g/L]). In the three patients who were not cured, the hemoglobin level at 6 months of follow-up was stable in the male patient and was slightly decreased in the two female patients. These three patients experienced mild fatigue. However, in all patients, a clear decrease in ferritin levels was observed (data not shown). Helicobacter pylori Gastritis At diagnosis, 7 patients had mild antral atrophic gastritis, of whom 4 had associated chronic, body nonatrophic gastritis; 1 patient had only body nonatrophic gastritis; and 22 patients had chronic antral nonatrophic gastritis, 20 of whom had a similar pattern in the gastric body mucosa. Thus, considering the involvement of both gastric compartments, 24 of 30 (80%) patients with iron de

Fecal Lactate and Ulcerative Colitis

Impaired metabolism of short-chain fatty acids, as well as a modified fecal ionogram, have been reported in ulcerative colitis. Fecal water samples from 62 patients with ulcerative colitis were analyzed in the present investigation to evaluate changes in SCFAs and lactic acid in relation to activity and severity of disease. Short-chain fatty acid levels were high in quiescent and mild disease (162.6 +/- 63.6 and 147.8 +/- 63.2 mM/L, respectively), but significantly decreased in the severe form (64.7 +/- 46.9 mM/L). Lactate showed a progressive increase from mild colitis (3.0 +/- 1.8 mM/L) to severe colitis (21.4 +/- 18.6 mM/L). It thus appears that mild colitis displayed a fecal pattern characterized by normal pH and bicarbonate, slightly impaired electrolyte handling, high short-chain fatty acid values, and only moderately increased lactate. Severe colitis, on the other hand, was characterized by low fecal pH, bicarbonate, and potassium, high sodium and chloride, low short-chain fatty acid levels, and very high lactate levels. A critical lowering of intraluminal pH, which shifts bacterial metabolism from short-chain fatty acid to lactate production, may be responsible for the intraluminal pooling of lactate.

Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial.

Background The treatment of distal ulcerative colitis, refractory to conventional 5‐ASA/steroid treatment, is still a matter of debate. The present study aimed at confirming, with adequate statistical power, previous data indicating the usefulness of topical butyrate and 5‐ASA in the treatment of this condition.

Short-chain fatty acid topical treatment in distal ulcerative colitis

Background: Some evidence indicates that short‐chain fatty acid (SCFA) enemas are effective in the treatment of distal ulcerative colitis.

Colectomy rate in acute severe ulcerative colitis in the infliximab era

BACKGROUND Severe ulcerative colitis is a potentially life-threatening condition. Due to advances in medical therapy, the mortality rate has dropped to <2% over the past 30 years, but the colectomy rate reaches 30%. Recently, infliximab has been shown to be effective as rescue therapy but little is known about long-term benefits. AIM To evaluate short-and long-term colectomy rates for severe ulcerative colitis in the era of biological treatment and to identify predictive factors of long-term colectomy. PATIENTS AND METHODS From 2001 to 2006 all in-patients with severe ulcerative colitis, according to Truelove and Witts criteria, were retrospectively reviewed. All patients had received intravenous steroid treatment; infliximab (5 mg/kg at 0, 2 and 6 weeks) was used as rescue therapy in steroid-refractory patients; colectomy was performed in patients who deteriorated whilst on steroid treatment or failed to respond to infliximab. RESULTS Of the 314 ulcerative colitis patients hospitalized during the study period, 52 (16.5%) met the criteria of severe ulcerative colitis. After median 7 days (range 4-15) on intravenous steroids, 37/52 (71%) patients showed a clinical response, while 15/52 (29%) were steroid-refractory. Of these, four underwent urgent colectomy and 11 received infliximab. A clinical response was observed in all infliximab-treated patients. In the long-term, another six patients underwent elective colectomy. The overall colectomy rate, following the acute attack, was 19%; the cumulative probability of a course without colectomy was 90%, 86%, 84%, 81%, after 6, 12, 18 and 24 months, respectively. No deaths occurred. The long-term colectomy risk was comparable in patients treated with infliximab and in steroid-responsive patients (18% vs. 11% respectively; OR 1.9; 95% CI 0.26-14.5). No predictive factors of colectomy, in the long-term, were identified. CONCLUSIONS Surgery continues to play an important role in acute severe ulcerative colitis. Infliximab can avoid urgent colectomy in steroid-refractory patients but the risk of elective colectomy, in the long-term, is not modified.

Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis

BACKGROUND AND AIM The treatment of ulcerative colitis (UC) with 5-aminosalicylic acid (5-ASA) does not have the same therapeutic effect in all patients. We tested the hypothesis that the effectiveness of the drug is related to its mucosal concentration. PATIENTS Twenty one UC patients receiving oral 5-ASA (2.4–3.2 g/day) were enrolled in the study. Four were also receiving topical treatment (2 g/day). METHODS Six endoscopic biopsies were taken from the rectum for measurement of 5-ASA concentrations (ng/mg) by HPLC; soluble interleukin 2 receptor (sIL-2R) concentrations (U/ml) were measured by ELISA and histology. Endoscopic and histological appearance was graded on a four point scale (0–3). The Wilcoxons rank test and Pearsons correlation coefficient were used for statistical analysis. RESULTS Mucosal concentrations of 5-ASA were significantly higher (p=0.03) in patients with endoscopic scores of 0–1 compared with those with scores of 2–3 (16.1 (range 10.2–45) v 5.5 (3.5–17.4), respectively) and in patients with lower histological inflammation compared with those with more severe scores (17.4 (10.5–45)v 8.9 (3.5–17.2), respectively) (p<0.01). In contrast, mucosal sIL2-R concentrations were significantly lower in patients with slight endoscopic and histological lesions than in those with more severe disease. A significative inverse correlation (r=−0.85) was found between 5-ASA and sIL-2R mucosal concentrations (p=0.00008). CONCLUSIONS In patients with UC, in the same area of the intestinal tract, we found that the higher the 5-ASA mucosal concentrations, the lower the IL-2R levels and endoscopic and histological scores. We hypothesise that maintenance of high mucosal 5-ASA concentrations in all colonic segments could contribute to improve clinical outcome in UC patients.

Increased proliferation and apoptosis of colonic epithelial cells in dextran sulfate sodium-induced colitis in rats

We have evaluated morphologic alterations and epithelial cell apoptosis and proliferation of colonic mucosa in the acute and chronic phases of DSS-induced colitis. Colitis was induced in Sprague-Dawley rats by 7 days of 4% DSS oral administration followed by 7 days of tap water for one, two, and three cycles. Control rats receved tap water only. Morphological changes in colonic mucosa were evaluated and scored by light and scanning electron microscopy. Apoptosis was studied by TUNEL assay and cell proliferation by Ki-67 immunoreaction. The expression of both proapoptotic (Fas, FasL, Bax, p53) and antiapoptotic (Bcl2) cellular proteins was determined by immunohistochemistry. Morphologic assessment showed the most severe colonic epithelial lesions and inflammation in the distal colon with a trend to increasing severity from the first to the third DSS cycle. In DSS rats, the epithelial apoptotic index increased 20-fold after the first cycle and 120-fold after the second and third cycles compared with the controls; in the same way, the expression index of proapoptotic proteins (Fas, FasL, Bax, p53) dramatically increased. The proliferative index increased about 40 to 60-fold compared to controls, with no difference among the three DSS cycles. In conclusion, DSS-induced colitis in rats, which has many structural and ultrastructural features similar to those seen in human ulcerative colitis, is a suitable model for studying increased epithelial apoptosis and proliferation. Further studies employing this model will permitt two hypotheses to be tested. (1) Increased apoptosis may lead to a breakdown of the epithelial barrier function and facilitate the mucosal invasion of intraluminal microorganisms and/or antigens. (2) Abnormal and persistent epithelial hyperproliferation could be causally related to the development of colorectal cancers in the setting of chronic colonic inflammation.